Compounds having activity as inhibitors of cytochrome P450RAI

ABSTRACT

Compounds having Formulas 5 and 6 wherein the symbols have the meaning defined in the specification are inhibitors of the cytochrome P450RAI (retinoic acid inducible) enzyme, and are used for treating diseases responsive to treatment by retinoids.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention is directed to novel compounds whichinhibit the enzyme cytochrome P450RAI. More particularly, the presentinvention is directed to compounds many of which are derivatives ofphenylacetic or heteroarylacetic acid, and which inhibit the enzymecytochrome P450RAI. Several compounds of the invention that have aninhibitory effect on the enzyme cytochrome P450RAI include a cyclopropylaryl, cyclopropylheteroaryl, cyclopropylaminoaryl, or (1-imidazolyl)methylaryl structure.

[0003] 2. Background Art

[0004] Compounds which have retinoid-like activity are well known in theart, and are described in numerous United States and other patents andin scientific publications. It is generally known and accepted in theart that retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil^(R), diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis. Retinoid compounds have relatively recently beenalso discovered to be useful for treating type II non-insulin dependentdiabetes mellitus (NIDDM).

[0005] Several compounds having retinoid-like activity are actuallymarketed under appropriate regulatory approvals in the United States ofAmerica and elsewhere as medicaments for the treatment of severaldiseases responsive to treatment with retinoids. Retinoic acid (RA)itself is a natural product, biosynthesized and present in a multitudeof human and mammalian tissues and is known to play an important rule inthe regulation of gene expression, tissue differentiation and otherimportant biological processes in mammals including humans. Relativelyrecently it has been discovered that a catabolic pathway in mammals,including humans, of natural retinoic acid includes a step ofhydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoicacid inducible).

[0006] Several inhibitors of CP450RAI have been synthesized ordiscovered in the prior art, among the most important ones ketoconazole,liarozole and R116010 are mentioned. The chemical structures of theseprior art compounds are provided below. It has also been noted in theprior art, that administration to mammals, including humans, of certaininhibitors of CP-450RAI results in significant increase in endogeneousRA levels, and further that treatment with CP450RAI inhibitors, forexample with liarozole, gives rise to effects similar to treatment byretinoids, for example amelioration of psoriasis.

[0007] The following publications describe or relate to theabove-summarized role of CP450RAI in the natural catabolism of RA, toinhibitors of CP-450RAI and to in vitro and in vivo experiments whichdemonstrate that inhibition of CP450RAI activity results in a increasesendogeneous RA levels and potential therapeutic benefits:

[0008] Kuijpers, et al., “The effects of oral liarozole on epidermalproliferation and differentiation in severe plaque psoriasis arecomparable with those of acitretin”, British Journal of Dermatology,(1998) 139: pp 380-389.

[0009] Kang, et al., “Liarozole Inhibits Human Epidermal Retinoid Acid4-Hydroxylase Activity and Differentially Augments Human Skin Responsesto Retinoic Acid and Retinol In Vivo”, The Journal of InvestigativeDermatology, (August 1996) Vol. 107, No. 2: pp 183-187.

[0010] VanWauwe, et al., “Liarozole, an Inhibitor of Retinoic AcidMetabolism, Exerts Retinoid-Mimetic Effects in Vivo”, The Journal ofPharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2: pp773-779.

[0011] De Porre, et al., “Second Generation Retinoic Acid MetabolismBlocking Agent (Ramba) R116010: Dose Finding in Healthy MaleVolunteers”, University of Leuven, Belgium, pp 30.

[0012] Wauwe, et al., “Ketoconazole Inhibits the in Vitro and in VivoMetabolism of All-Trans-Retinoic Acid”, The Journal of Pharmacology andExperimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.

[0013] White, et al., “cDNA Cloning of Human Retinoic Acid-metabolizingEnzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450(CYP26)*”, The Journal of Biological Chemistry, (1997) Vol. 272, No. 30,Issue of July 25 pp 18538-18541.

[0014] Hanzlik, et al., “Cyclopropylamines as Suicide Substrates forCytochromes P450RAI”, Journal of Medicinal Chemistry (1979), Vol. 22,No. 7, pp 759-761.

[0015] Ortiz de Montellano, “Topics in Biology—The Inactivation ofCytochrome P450RAI”, Annual Reports in Medicinal Chemistry, (1984),Chapter 20, pp 201-210.

[0016] Hanzlik, et al. “Suicidal Inactivation of Cytochrome P450RAI byCyclopropylamines>Evidence for Cation-Radical Intermediates”, J. Am.Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052.

[0017] The present invention provides several new chemical compoundswhich act as inhibitors of CP450RAI, and as such potentially providetherapeutic benefit in the treatment or prevention of the diseases andconditions which respond to treatment by retinoids and or which inhealthy mammals, including humans, are controlled by natural retinoicacid. The perceived mode of action of these compounds is that byinhibiting the enzyme CP450RAI that catabolyzes natural RA, endogenousRA level is elevated to a level where desired therapeutic benefits areattained. The chemical structures of the compounds of the invention andof compounds with similar biological activity are summarized by Formulas1 through 8 which are provided in the Summary Section of thisapplication for patent. Based on these chemical structures the followingart is of interest as background to the novel structures.

[0018] U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357;5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795;4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0619 116; DE 3524199; Derwent JP6072866; Dawson, et al. “Chemistry andBiology of Synthetic Retinoids”, published by CRC Press Inc., (1990),pages 324-356; are of interest to compounds of Formula 5.

[0019] U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357;5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795;4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0619 116; DE 3524199; Derwert JP6072866; Dawson, et al. “Chemistry andBiology of Synthetic Retinoids”, published by CRC Press, Inc., (1990),pages 324-356; are of interest to compounds of Formula 6.

SUMMARY OF THE INVENTION

[0020] The present invention relates to compounds of Formula 5 and 6.The remaining formulas in this Summary section are of compounds havingthe same or similar biological activity. Those compounds are disclosedherein because their preparation involves synthetic routes which areillustrative of synthetic methodology that can be used for the synthesisof the compounds of Formulas 5 and 6 as well.

[0021] Compounds of Formula 1 are disclosed

[0022] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0023] X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;

[0024] Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons, Cl, Br, or I;

[0025] Z is —C≡C—,

[0026] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0027] —CO—NR₁—,

[0028] NR₁—CO—;

[0029] —CO—O—,

[0030] —O—CO—,

[0031] —CS—NR₁—,

[0032] NR₁—CS—,

[0033] —CO—S—,

[0034] —S—CO—,

[0035] —N═N—;

[0036] R₁ is independently H or alkyl of 1 to 6 carbons;

[0037] p is an integer having the values of 0 to 4;

[0038] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0039] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

[0040] m is an integer having the values 0 to 2;

[0041] R₄ is independently H, alkyl of 1 to 6 carbons, or F;fluorosubstituted alkyl of 1 to 6 carbons, or halogen;

[0042] o is an integer having the values of 0 to 2;

[0043] n is an integer having the values of 0 to 4, and

[0044] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base.

[0045] Compounds of Formula 2 are disclosed

[0046] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0047] X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;

[0048] Z is —C≡C—,

[0049] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0050] —CO—NR₁—,

[0051] NR₁—CO—;

[0052] —CO—O—,

[0053] —O—CO—,

[0054] —CS—NR₁—,

[0055] NR₁—CS—,

[0056] —CO—S—,

[0057] —S—CO—,

[0058] —N═N—;

[0059] R₁ is independently H or alkyl of 1 to 6 carbons;

[0060] p is an integer having the values of 0 to 4;

[0061] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

[0062] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

[0063] m is an integer having the values 0 to 4;

[0064] R₅ is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to6 carbons, benzyl, or lower alkyl or halogen substituted benzyl;

[0065] n is an integer having the values of 0 to 4, and

[0066] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base.

[0067] Compounds of Formula 3 are disclosed

[0068] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0069] Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 1 to6 carbons, Cl, Br, or I;

[0070] Z is —C≡C—,

[0071] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0072] —CO—NR₁—,

[0073] NR₁—CO—;

[0074] —CO—O—,

[0075] —O—CO—,

[0076] —CS—NR₁—,

[0077] NR₁—CS—,

[0078] —CO—S—,

[0079] —S—CO—,

[0080] —N═N—;

[0081] R₁ is independently H or alkyl of 1 to 6 carbons;

[0082] p is an integer having the values of 0 to 5;

[0083] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

[0084] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

[0085] m is an integer having the values 0 to 2;

[0086] R₄ is independently H, alkyl of 1 to 6 carbons, or F;fluorosubstituted alkyl of 1 to 6 carbons, or halogen;

[0087] o is an integer having the values of 0 to 4;

[0088] n is an integer having the values of 0 to 4, and

[0089] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base.

[0090] Compounds of Formula 4 are disclosed

[0091] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0092] X₁ is 1-imidazolyl, or lower alkyl or halogen substituted1-imidazolyl, OR, SR, NRR₆ where R is H, alkyl of 1 to 6 carbons orbenzyl;

[0093] Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons, Cl, Br, or I;

[0094] Z is —C≡C—,

[0095] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0096] —CO—NR₁—,

[0097] NR₁—CO—;

[0098] —CO—O—,

[0099] —O—CO—,

[0100] —CS—NR₁—,

[0101] NR₁—CS—,

[0102] —CO—S—,

[0103] —S—CO—,

[0104] —N═N—;

[0105] R₁ is independently H or alkyl of 1 to 6 carbons;

[0106] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

[0107] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

[0108] m is an integer having the values 0 to 2;

[0109] R₄ is independently H, alkyl of 1 to 6 carbons, or F;fluorosubstituted alkyl of 1 to 6 carbons, or halogen;

[0110] o is an integer having the values of 0 to 4;

[0111] R₆ is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkylsubstituted cycloalkyl of 3 to 6 carbons;

[0112] n is an integer having the values of 0 to 4, and

[0113] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base, with the proviso that when Y isH, A is phenyl and X₁ is OH then n is 1 to 4.

[0114] The present invention relates to compounds of Formula 5

[0115] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0116] X is O, S or NR where R is H, alkyl of 1 to 6 carbons,C₁₋₆-trialkylsilyl or benzyl;

[0117] Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons, Cl, Br, or I;

[0118] Z is —C≡C—,

[0119] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0120] —CO—NR₁—,

[0121] NR₁—CO—;

[0122] —CO—O—,

[0123] —O—CO—,

[0124] —CS—NR₁—,

[0125] NR₁—CS—,

[0126] —CO—S—,

[0127] —S—CO—,

[0128] —N═N—;

[0129] R₁ is independently H or alkyl of 1 to 6 carbons;

[0130] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

[0131] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

[0132] m is an integer having the values 0 to 3;

[0133] R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons orlower alkyl substituted cycloalkyl of 1 to 6 carbons;

[0134] n is an integer having the values of 1 to 4, and

[0135] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base.

[0136] The present invention also relates to compounds of Formula 6

[0137] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0138] X₂ is 1-imidazolyl, lower alkyl or halogen substituted1-imidazolyl, OR₇, SR₇ or NRR₇ where R is H, alkyl of 1 to 6 carbons orbenzyl;

[0139] Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons, Cl, Br, or I;

[0140] Z is —C≡C—,

[0141] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0142] —CO—NR₁—,

[0143] NR₁—CO—;

[0144] —CO—O—,

[0145] —O—CO—,

[0146] —CS—NR₁—,

[0147] NR₁—CS—,

[0148] —CO—S—,

[0149] —S—CO—,

[0150] —N═N—;

[0151] R₁ is independently H or alkyl of 1 to 6 carbons;

[0152] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, oralkylthio of 1 to 6 carbons;

[0153] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons,alkylthio of 1 to 6 carbons or benzyl;

[0154] m is an integer having the values 0 to 3;

[0155] R₇ is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons,lower alkyl substituted cycloalkyl of 3 to 6 carbons orC₁₋₆-trialkylsilyl.

[0156] n is an integer having the values of 0 to 4, and

[0157] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base.

[0158] Compounds of Formula 7 are disclosed

[0159] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0160] Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons, F, Cl, Br, or I;

[0161] Z is —C≡C—,

[0162] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0163] —CO—NR₁—,

[0164] NR₁—CO—;

[0165] —CO—O—,

[0166] —O—CO—,

[0167] —CS—NR₁—,

[0168] NR₁—CS—,

[0169] —CO—S—,

[0170] —S—CO—,

[0171] —N═N—;

[0172] R₁ is independently H or alkyl of 1 to 6 carbons;

[0173] p is an integer having the values of 0 to 5;

[0174] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0175] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl;

[0176] m is an integer having the values 0 to 2;

[0177] R₄ is independently H, alkyl of 1 to 6 carbons, or F;fluorosubstituted alkyl of 1 to 6 carbons, or halogen;

[0178] o is an integer having the values of 0 to 4;

[0179] n is an integer having the values of 0 to 4, and

[0180] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base.

[0181] Compounds of Formula 8 are disclosed

[0182] wherein A is a phenyl or naphthyl group, or heteroaryl selectedfrom a group consisting of pyridyl, thienyl, furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl,said phenyl and heteroaryl groups being optionally substituted with oneor two R₂ groups;

[0183] X₃ is S, or O, C(R₁)₂, or CO;

[0184] Y₁, is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;

[0185] Z is —C≡C—,

[0186] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 1-5,

[0187] —CO—NR₁—,

[0188] NR₁—CO—;

[0189] —CO—O—,

[0190] —O—CO—,

[0191] —CS—NR₁—,

[0192] NR₁—CS—,

[0193] —CO—S—,

[0194] —S—CO—,

[0195] —N═N—;

[0196] R₁ is independently H or alkyl of 1 to 6 carbons;

[0197] R₂ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I,CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0198] R₃ is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, alkylthio of 1 to 6 carbons or benzyl;

[0199] m is an integer having the values 0 to 2;

[0200] R₄ is independently H, alkyl of 1 to 6 carbons, or F;fluorosubstituted alkyl of 1 to 6 carbons, or halogen;

[0201] o is an integer having the values of 0 to 4;

[0202] n is an integer having the values of 0 to 4, and

[0203] R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or a cationof a pharmaceutically acceptable base, the compound meeting at least oneof the provisos selected from the group consisting of:

[0204] Y₁ is cycloalkyl,

[0205] when Y₁ is not cycloalkyl then X₃ is O or S and n is 1,

[0206] when Y₁ is not cycloalkyl then X₃ is CO, and n is 1,

[0207] when Y₁ is not cycloalkyl then X₃ is CO and the moiety A issubstituted with at least one F group.

[0208] In a second aspect, this invention relates to the use of thecompounds of Formulas 5 and 6 for the prevention or treatment ofdiseases and conditions in mammals, including humans, which diseases orconditions are prevented, treated, ameliorated, or the onset of which isdelayed by administration of retinoid compounds or by the mammalianorganism's naturally occurring retinoic acid. Because the compounds actas inhibitors of the breakdown of retinoic acid, the invention alsorelates to the use of the compounds of Formulas 5 and 6 in conjunctionwith retinoic acid or other retinoids. In this regard it is noted thatretionoids are useful for the treatment of skin-related diseases,including, without limitation, actinic keratoses, arsenic keratoses,inflammatory and non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The retinoidsare also useful for the prevention and treatment of metabolic diseasessuch as type II non-insulin dependent diabetes mellitus (NIDDM) and forprevention and treatment of cancerous and precancerous conditions,including, premalignant and malignant hyperproliferative diseases suchas cancers of the breast, skin, prostate, cervix, uterus, colon,bladder, esophagus, stomach, lung, larynx, oral cavity, blood andlymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias andpapillomas of the mucous membranes and in the treatment of Kaposi'ssarcoma. Retinoids can also be used as agents to treat diseases of theeye, including, without limitation, proliferative vitreoretinopathy(PVR), retinal detachment, dry eye and other corneopathies, as well asin the treatment and prevention of various cardiovascular diseases,including, without limitation, diseases associated with lipid metabolismsuch as dyslipidemias, prevention of post-angioplasty restenosis and asan agent to increase the level of circulating tissue plasminogenactivator (TPA). Other uses for retinoids include the prevention andtreatment of conditions and diseases associated with human papillomavirus (HPV), including warts and genital warts, various inflammatorydiseases such as pulmonary fibrosis, ileitis, colitis and Krohn'sdisease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil^(R), diseases associated with the immune system, including useof the present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

[0209] This invention also relates to a pharmaceutical formulationcomprising one or more compounds of Formulas 5 and 6 in admixture with apharmaceutically acceptable excipient, said formulation being adaptedfor administration to a mammal, including a human being, to treat oralleviate the conditions which were described above as treatable byretinoids, or which are controlled by or responsive to the organism'snative retinoic acid. These formulations can also be co-administeredwith retinoids to enhance or prolong the effects of medicationscontaining retinoids or of the organism's native retinoic acid.

BRIEF DESCRIPTION OF THE DRAWING FIGURE

[0210]FIG. 1 is a schematic representation of the P450RAI cell basedassay utilized to evaluate the ability of the compounds of the inventionto inhibit the Cytochrome P450RAI enzyme.

BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION P450RAI-1 Cell-BasedInhibitor Assay

[0211]FIG. 1 shows a schematic diagram of the P450RAI-1 cell basedassay. P450RAI-1 stably transfected HeLa cells are maintained in 100millimolar tissue culture dishes in Modified Eagle's Medium (MEM)containing 10% Fetal Bovine Serum (FBS) and 100 μg/ml hygromycin.Exponentially growing cells are harvested by incubating in trypsin.Cells are then washed with 1×Phosphate Buffered Saline (PBS) and platedin a 48-well plate at 5×10⁵ cells in 0.2 ml MEM medium containing 10%FBS and 0.05 μCi [³H]-RA in the presence or absence of increasingconcentrations of the test compounds. The compounds are diluted in 100%DMSO and then added in triplicate wells at either 10, 1 or 0.1 μM finalconcentration. As a positive control for RA metabolism inhibition, cellsare also incubated with ketoconazole at 100, 10 and 1 μM. Cell areincubated for 3 hours at 37° C. The retinoids are then extracted usingthe procedure of Bligh et al. (1959) Canadian Journal of Biochemistry37, 911-917, modified by using methylenechloride instead of chloroform.The publication Bligh et al. (1959) Canadian Journal of Biochemistry 37,911-917 is specifically incorporated herein by reference. The watersoluble radioactivity is quantified using a β-scintillation counter.IC₅₀ values represent the concentration of inhibitor required to inhibitall-trans-RA metabolism by 50 percent and are derived manually fromlog-transformed data. The IC₅₀ values obtained in this assay for severalpreferred compounds of the invention are disclosed in Table 1 below.

[0212] Assays of Retinoid-like or Retinoid Antagonist and InverseAgonist-like Biological Activity

[0213] Assays described below measure the ability of a compound to bindto, and/or activate various retinoid receptor subtypes. When in theseassays a compound binds to a given receptor subtype and activates thetranscription of a reporter gene through that subtype, then the compoundis considered an agonist of that receptor subtype. Conversely, acompound is considered an antagonist of a given receptor subtype if inthe below described co-tranfection assays the compound does not causesignificant transcriptional activation of the receptor regulatedreporter gene, but nevertheless binds to the receptor with a K_(d) valueof less than approximately 1 micromolar. In the below described assaysthe ability of the compounds to bind to RAR_(α), RAR_(β), RAR_(γ),RXR_(α), RXR_(β) and RXR_(γ) receptors, and the ability or inability ofthe compounds to activate transcription of a reporter gene through thesereceptor subtypes can be tested.

[0214] As far as specific assays are concerned, a chimeric receptortransactivation assay which tests for agonist-like activity in theRAR_(α), RAR_(β), and RAR_(γ), receptor subtypes, and which is based onwork published by Feigner P. L. and Holm M. (1989) Focus, 112 isdescribed in detail in U.S. Pat. No. 5,455,265. The specification ofU.S. Pat. No. 5,455,265 is hereby expressly incorporated by reference.The numeric results obtained with several preferred compounds of thisinvention in this assay are shown below in Table 1. These datademonstrate that generally speaking the compounds are not agonists (oronly weak agonists) of RAR retinoic receptors, and also that they do notbind, or in some cases bind only weakly to RAR retinoid receptors.

[0215] A holoreceptor transactivation assay and a ligand binding assaywhich measure the antagonist/agonist like activity of the compounds ofthe invention, or their ability to bind to the several retinoid receptorsubtypes, respectively, are described in published PCT Application No.WO WO93/11755 (particularly on pages 30-33 and 37-41) published on Jun.24, 1993, the specification of which is also incorporated herein byreference. A detailed experimental procedure for holoreceptortransactivations has been described by Heyman et al. Cell 68, 397-406,(1992); Allegretto et al. J. Biol. Chem. 268, 26625-26633, andMangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp319-349, Raven Press Ltd., New York, which are expressly incorporatedherein by reference. The results obtained in this assay are expressed inEC₅₀ numbers, as they are also in the chimeric receptor transactivationassay. The results of ligand binding assay are expressed in K_(d)numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp3099-3108, expressly incorporated herein by reference.)

[0216] The results if the ligand binding assay for several preferredcompounds of the invention are included in Table 1. In the holoreceptortransactivation assay, tested for RXR_(α), RXR_(β), and RXR_(γ)receptors, the compounds of the present invention are, generallyspeaking, entirely devoid of activity, demonstrating that the compoundsof the invention do not act as RXR agonists. TABLE 1 P450RAI INHIBITIONCom- RAR DATA pound General Table EC₅₀ /(EFFICACY)/K_(d)nM INTACT HELA #Formula #¹ α β Υ IC₅₀μM 110 2 3 NA 74 262 >10 (44) (42) >10 2058409 >10K 112 2 3 NA 335 NA >10 (37) 5853 704 685 3 4 5 280 4.8 9.8 3(28) (54) (52) 145 0.8 158 114 2 3 NA NA NA >10 >10K >10K >10K 108 2 36.6 283 141 >10 (15) (36) (10) 21K 547 13K 116 2 3 NA WA NA >10 3269 732886 77 2 3 NA WA NA >10 2207 225 16 78 2 3 NA NA NA >10 >10K >10K >10K40 1 2 33 1.2 6.8 1.7 (207) (126) (140) 69 1.3 363 42 1 2 NA NA NA 0.1915K 3636 >10K 28 8 9 NA NA NA 0.34 21K 4272 >10K 70 2 3 NA NANA >10 >10K >10K >10K 69 2 3 313 12 52.6 >10 (10) (50) (31) 469 133 50173 2 3 WA 22.5 91 >10 (39) (24) 486 26 351 74 2 3 NA NA NA 3.5 11K14K >10K 30 8 9 0.28 14 2.2 84 44 1 2 49 1.7 7.5 0.27 (138) (100) (116)37 1.9 392 82 2 3 NA NA NA >10 >10K >10K >10K 81 2 3 NA 490 183 >10 (80)(67) 4210 846 1058 89 2 3 268 26 12 >10 (20) (50) (46) 3407 980 475 90 23 NA NA NA 0.95 >10K >10K >10K 94 2 3 NA NA NA >10 >10K >10K >10K 93 2 34821 20 10 (114) (39) (55) >10 3450 554 358 5 8 9 NA 11 NA 0.55 (36)9148 2815 >10K 8 4 5 NA 363 NA 0.4 (96) 10K 3781 25K 86 2 3 NA NA NA1.4 >10K >10K >10K 85 2 3 976 3.5 2.5 >10 (60) (77) (65) 1861 240 302 982 3 NA NA NA 0.8 13 4 5 NA 3.2 116 3.1 (6.6) (9) 10 8 9 57 0.3 6 0.7(146) (86) (94) 36 8 9 0.033 13K 4896 492 38 8 9 0.025 10K 5317 2884 348 9 0.13 61.5 15 2.5 119 6 7 0.4 >10K >10K >10K 121 6 70.18 >10K >100K >100K 46 8 9 2.2 >10K >10K >10K 20 8 9 >10 18 4 5 1.1 328 9 0.18 27K 4225 13K 139 4 5 0.05 22 3 4 1.6 24 3 4 3 137 4 5 0.1 26 45 10 127 6 7 0.4 126 6 7 0.09 48 1 2 0.03 50 1 2 0.014 52 1 2 0.05 54 12 0.022 62 7 8 >10 56 8 9 0.13 134 6 7 5 58 1 2 0.18 60 1 2 1.6 143 0.8145 0.2

[0217] Topical Skin Irritation Tests

[0218] As is known the topical retinoid all-trans-retinoic acid (ATRA)and oral retinoids such as 13-cis RA and etretinate are known to inducesubstantial skin irritation in humans. This irritation is a directresult of activation of the RAR nuclear receptors. Analysis of retinoidtopical irritation is also a highly reproducible method of determiningin vivo retinoid potency. The SKH1-hrBR or hairless mouse provides aconvenient animal model of topical irritation, since retinoid-inducedskin flaking and abrasion can be readily scored by eye (Standeven etal., “Specific antagonist of retinoid toxicity in mice.” Toxicol. Appl.Pharmacol., 138:169-175, (1996); Thacher, et al., “Receptor specificityof retinoid-induced hyperplasia. Effect of RXR-selective agonists andcorrelation with topical irritation”. J. Pharm. Exp. Ther., 282:528-534,(1997)). As is demonstrated below the topical application of P450RAIinhibitors of the present invention also causes an increase in theendogenous levels of ATRA that results in ATRA-induced irritation inskin of hairless mice. The attached data table discloses theretinoid-mimetic effects of some P450RAI inhibitor compounds of thepresent invention on the skin of hairless mice.

[0219] Methods

[0220] Female hairless mice (Crl :SKH1-hrBR), 5-7 weeks old, wereobtained from Charles River Breeding Labs (Wilmington, Mass.). Animalswere about 6 weeks old at the start of the experiments. Food (PurinaRodent Chow 5001) and reverse osmosis water were provided ad libitum.Mice were housed individually throughout the dosing period. In someexperiments, mice that fit within a defined weight range, e.g., 21-25 g,were selected from the available stock and then randomly assigned to thevarious treatment groups, using body weight as the randomizationvariable.

[0221] The compounds to be tested were dissolved in acetone forapplication to the backs of the mice.

[0222] Mice were treated topically on the back in a volume of 4.0 ml/kg(0.07-0.12 ml) adjusted daily so as to deliver a fixed dose of testcompound per g body weight. Doses are disclosed as nmol/25 g.

[0223] Unless indicated otherwise, mice were treated with retinoids oncedaily on days 1 through 5 and observed on days 2, 3, 4, 5, 6, 7 and 8.

[0224] The mice were weighed daily and the dorsal skin was graded dailyusing separate semi-quantitative scales to determine flaking andabrasion. These flaking and abrasion scores were combined with weightchange (if any) to create a cutaneous toxicity score (Blackjack score).

[0225] Cutaneous Toxicity Score

[0226] A visual grading scale was used for characterizing topicalirritation on a daily basis. The grading scale used is as follows:Flaking Abrasions 0 = none 0 = none 1 = slight (small flakes, <50% 1 =slight (one or two abrasions coverage) with a light pink color) 2 = mild(small flakes, 50% 2 = mild (several abrasions with a coverage) pinkcolor) 3 = moderate (small flakes, >50% 3 = moderate (one or two deepcoverage & large flakes, <25% abrasions with red color, <25% coverage)coverage) 4 = severe (small flakes, >50% 4 = severe (multiple deepabrasions coverage & large flakes, 25-50% with red color, >25% coverage)coverage) 5 = very severe (large flakes, >50% coverage)

[0227] Topical Toxicity Score

[0228] The flaking and abrasion observations were combined with bodyweight observations to calculate a single, semiquantitative topical orcutaneous “toxicity score” as detailed below. The toxicity score (alsoknown as “blackjack score” since the theoretical maximum is 21) takesinto account the maximal severity, and the time of onset of skin flakingand abrasions and the extent of weight between the first and last daysof the experiment. Below are listed the seven numerical components ofthe toxicity score and an explanation of how those values are combinedto calculate the toxicity score. 1. Flaking-Maximal Severity: Highestflaking score attained during observation period. 2. Flaking-Day ofOnset of grade 2 or worse: 0->8 days 1-day 8 2-day 6 or 7 3-day 4 or 54-day 2 or 3 3. Flaking-Average Severity: Flaking severity scores aresummed and divided by the number of observation days. 4.Abrasion-Maximal Severity: Highest abrasion score attained duringobservation period. 5. Abrasion-Day of Onset of grade 2 or worse: Samescale as (2) above. 6. Abrasion-Average Severity: Abrasion severityscores are summed and divided by the number of observation days. 7.Systemic Toxicity (weight loss): 0-<1 g 1-1 to 2 g 2-2 to 4 g 3-4 to 6 g4->6 g or dead

[0229] Calculation of Composite Flaking Score

[0230] Flaking onset score (2) and average severity score (3) are summedand divided by two. The quotient is added to the maximal severity score(1). Composite flaking scores are calculated for each individual animalin a group, averaged, and rounded to the nearest integer. Values canrange from 0-9.

[0231] Calculation of Composite Abrasion Score

[0232] Abrasion onset score (5) and average severity score (6) aresummed and divided by two. The quotient is added to the maximal severityscore (4). Composite abrasion scores are calculated for each individualanimal in a group, averaged and rounded to the nearest integer. Valuescan range from 0-8.

[0233] Calculation of Toxicity Score

[0234] Composite flaking score, composite abrasion score, and systemictoxicity score are summed to give the “toxicity score.” Toxicity scoresare calculated for each individual animal in a group, averaged, androunded to the nearest integer. Values can range from 0-21 and areexpressed in Table 1A below as the mean±SD of the values for a group.

[0235] Calculation of Percentage Change in Body Weight

[0236] The body weight at the time of the last weighing (day 8, 11, or12) was subtracted from the initial body weight. The difference wasdivided by the initial body weight, multiplied by 100%, and rounded tothe nearest integer. Values were calculated for each individual animaland the mean and standard deviation for each group are shown. TABLE 1ACutaneous Toxicity Score (Blackjack Score) 100 300 1000 Compound No.nmole nmole nmole 5 0 6 ± 3 15 1 ± 1 5 ± 2 36 1 ± 1 11 ± 0  38 1 ± 1 10± 1  8 5 ± 2 8 ± 3 12 ± 1  22 0 ± 0 0 ± 0 1 ± 1 137 1 ± 1 1 ± 1 5 ± 2 481 ± 1 3 ± 1 7 ± 2 50 1 ± 0 3 ± 2 8 ± 2 58 0 ± 0 0 ± 0 0 ± 0 131 1 ± 1 0± 1 1 ± 1 127 0 ± 0 0 ± 0 0 ± 0 18 0 ± 0 5 ± 2 10 ± 2 

[0237] Modes of Administration

[0238] The compounds of this invention may be administered systemicallyor topically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations. Thus, in the treatmentof dermatoses, it will generally be preferred to administer the drugtopically, though in certain cases such as treatment of severe cysticacne or psoriasis, oral administration may also be used. Any commontopical formulation such as a solution, suspension, gel, ointment, orsalve and the like may be used. Preparation of such topical formulationsare well described in the art of pharmaceutical formulations asexemplified, for example, by Remington's Pharmaceutical Science, Edition17, Mack Publishing Company, Easton, Pa. For topical application, thesecompounds could also be administered as a powder or spray, particularlyin aerosol form. If the drug is to be administered systemically, it maybe confected as a powder, pill, tablet or the like or as a syrup orelixir suitable for oral administration. For intravenous orintraperitoneal administration, the compound will be prepared as asolution or suspension capable of being administered by injection. Incertain cases, it may be useful to formulate these compounds byinjection. In certain cases, it may be useful to formulate thesecompounds in suppository form or as extended release formulation fordeposit under the skin or intramuscular injection.

[0239] Other medicaments can be added to such topical formulation forsuch secondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

[0240] Treatment of dermatoses or any other indications known ordiscovered to be susceptible to treatment by retinoic acid-likecompounds, or to control by naturally occurring retinoic acid will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the compoundpotentially may be used in prophylactic manner to prevent onset of aparticular condition.

[0241] A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg of body weight per day would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

[0242] In some applications pharmaceutical formulations containing theCP-450RAI inhibitory compounds of the invention may be co-administeredwith formulations containing retinoids.

[0243] General Embodiments and Synthetic Methodology

[0244] Definitions

[0245] The term alkyl refers to and covers any and all groups which areknown as normal alkyl and branched-chain alkyl. Unless specifiedotherwise, lower alkyl means the above-defined broad definition of alkylgroups having 1 to 6 carbons in case of normal lower alkyl, and 3 to 6carbons for lower branch chained alkyl groups. A pharmaceuticallyacceptable salt may be prepared for any compound in this inventionhaving a functionality capable of forming a salt, for example an acidfunctionality. A pharmaceutically acceptable salt is any salt whichretains the activity of the parent compound and does not impart anydeleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

[0246] Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri-acid may also be used.

[0247] Some compounds of the present invention may have trans and cis (Eand Z) isomers. Unless specific orientation of substituents relative toa double bond or a ring is indicated in the name of the respectivecompound, and/or by specifically showing in the structural formula theorientation of the substituents relative to the double bond or ring theinvention covers trans as well as cis isomers.

[0248] Some of the compounds of the present invention may contain one ormore chiral centers and therefore may exist in enantiomeric anddiastereomeric forms. The scope of the present invention is intended tocover all isomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well. A bond drawn with a wavy line indicates that thecarbon to which the bond is attached can be in any of the applicablepossible configurations.

[0249] General Synthetic Methodology

[0250] The compounds of the invention are encompassed by the generalFormulas 1 through 8 provided above. As it can be seen, in each of theseformulas a linker or tethering group designated Z covalently connects anaromatic or heteroaromatic moiety designated A(R₂)—CH₂)_(n)—COOR₈ andanother cyclic moiety which in accordance with these formulas is asubstituted phenyl, substituted tetrahydronaphthalene, substitutedchroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinolinemoiety. Generally speaking a compound such as X₄-A(R₂)—CH₂)_(n)—COOR₈ iscommercially available, or can be made in accordance with the chemicalliterature, or with such modification of known chemical processes whichare within the skill of the practicing organic chemist. The group X₄represents a reactive group, which is suitable for coupling theX₄₋A(R₂)—CH₂)_(n)—COOR₈ compound to a derivative of the substitutedphenyl, substituted tetrahydronaphthalene, substituted chroman,thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety sothat as a result of the coupling the linker or tether moiety Z isformed. In many instances the group X₄ is a leaving group such ashalogen, or trifluoromethanesulfonyloxy, or a group capable ofparticipating in a Wittig or Horner Emmons reaction. In some instancesthe group X₄ is an ethynyl group capable of undergoing a couplingreaction with a leaving group (such as a halogen or atrifluoromethanesulfonyloxy group) attached to the substituted phenyl,substituted tetrahydronaphthalene, substituted chroman, thiochroman,tetrahydroquinoline or tetrahydroisoquinoline moiety. The group X₄ canalso represent an OH or an NH₂ group that forms an ester (COO) or amide(CONH) linker, respectively, when reacted with an activated carboxylderivative of the substituted phenyl, substituted tetrahydronaphthalene,substituted chroman, thiochroman, tetrahydroquinoline ortetrahydroisoquinoline moiety. Examples for the compounds of formulaX₄₋A(R₂)—CH₂)_(n)—COOR₈ are provided in the specific examples below.Further examples where the X₄ group is halogen are ethyl 4-iodobenzoate,ethyl 6-iodonicotinate, ethyl 5-iodofuran-3-carboxylate, ethyl5-iodothiophen-3-carboxylate, ethyl 5-iodofuran-2-carboxylate, ethyl5-iodothiophen-2-carboxylate, and analogous halogenated derivatives ofthe respective pyridazine, pyrazine and other heteroaryl carboxylic acidesters. The analogous aryl and heteroaryl hydroxyl compounds and amines,wherein the halogen of the above-listed compounds is replaced by OH orNH₂ respectively, also serve as additional examples for the reagents ofthe formula X₄-A(R₂)—CH₂)_(n)—COOR₈. In these examples X₄ is OH or NH₂,respectively.

[0251] Still further in accordance with the general syntheticmethodology to provide the compounds of the present invention, aderivative of the substituted phenyl, substituted tetrahydronaphthalene,substituted chroman, thiochroman, tetrahydroquinoline ortetrahydroisoquinoline moiety is synthesized first, having a covalentlyattached X₅ group. The X₅ group reacts with the X₄ group of the reagentX₄-A(R₂)—CH₂)_(n)—COOR₈ to form the linker designated Z in Formulas 1through 8. The X₅ group is one that is capable of participating in acatalyzed coupling reaction, (such as an ethynyl group when X₄ is aleaving group), or a leaving group (such as halogen ortrifluoromethanesulfonyloxy when X₄ is an ethynyl group), or anactivated carboxylic acid function (when X₄ is OH or NH₂). The X₅ groupcan also be an OH, SH or NH₂ group when the X₄ group is an activatedcarboxylic acid function. Specific examples for substituted phenyl,substituted tetrahydronaphthalene, substituted chroman, thiochroman,tetrahydroquinoline or tetrahydroisoquinoline intermediates having an X₅functionality are provided below, and are also available in the chemicalscientific and patent literature. Generally speaking, for reagents andreactions covalently joining a substituted tetrahydronaphthalene,substituted chroman, thiochroman, or tetrahydroquinoline intermediatewith a substituted aryl or heteroaryl group, such asX₄-A(R₂)—CH₂)_(n)—COOR₈, to form a compound including the linkerdesignated Z, reference is made to U.S. Pat. Nos. 5,648,503; 5,723,666and 5,952,345 the specification of each of which are expresslyincorporated herein by reference.

[0252] The substituted phenyl, tetrahydronaphthalene, chroman,thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety of thenovel compounds of the invention are derivatized in a manner to includethe specific substituents (such as for example the cycloalkylsubstituents) encompassed within the scope of the invention, eitherbefore or after the -A(R₂)—CH₂)_(n)—COOR₈ moiety has been attached andthe linker Z has formed, as illustrated by the below described specificexamples.

[0253] The —CH₂)_(n)—COOR₈ moiety of the compounds of the invention canbe modified in order to obtain still further compounds of the invention.One such modification is saponification of compounds where the R₈ groupis an alkyl or —CH₂O(C₁₋₆-alkyl) group. Another modification isesterification of the carboxylic acid function when the R₈ group is H ora cation. Such saponification and esterification reactions are wellknown in the art and within the skill of the practicing organic chemist.Still another modification of the compounds of the invention (or of theintermediates X₄-A(R₂)—CH₂)_(n)—COOR₈, or of precursors to theseintermediates) is the homologation of the (CH₂)_(n) group. The lattercan be accomplished, for example, by the well known Arndt-Eistert methodof homologation, or other known methods of homologation.

[0254] Specific Embodiments

[0255] With reference to the symbol A in Formulas 1 through 8, thepreferred compounds of the invention are those where A is phenyl,naphthyl, pyridyl, thienyl or furyl. Even more preferred are compoundswhere A is phenyl. As far as substitutions on the A (phenyl) and A(pyridyl) groups are concerned, compounds are preferred where the phenylgroup is 1,4 (para) substituted and where the pyridine ring is 2,5substituted. (Substitution in the 2,5 positions in the “pyridine”nomenclature corresponds to substitution in the 6-position in the“nicotinic acid” nomenclature.) In the presently preferred compounds ofthe invention either there is no R₂ substituent on the A group, or theR₂ substituent is preferably a fluoro group that is preferably locatedon the aromatic carbon adjacent (ortho) to the carbon bearing the—(CH₂)_(n)—COOR₈ group.

[0256] As far as the —(CH₂)_(n)—COOR₈ is concerned compounds arepreferred where n is 0, 1 or 2, and even more preferred where n is 1. InFormulas 5 and 8 only compounds where n is 1 or 2 are preferred, withn=1 being most preferred. For the R₈ group H, lower alkyl of 1 to 3carbons, and —CH₂O(C₁₋₆-alkyl) groups are preferred, as well as thepharmaceutically acceptable salts of the free acids when R₈ is H. Amongthe lower alkyl and —CH₂O(C₁₋₆-alkyl) groups ethyl and OCH₂CH₃,respectively, are presently most preferred.

[0257] The linker group Z in all the compounds of the invention ispreferably ethynyl (—C≡C—), ester (CO—O), ethenyl, (—CR₁═CR₁—) or amide(CONR₁). Among these the ethynyl (—C≡C—) and ester (CO—O) linkers aremost preferred. Moreover, in the preferred compounds of the inventionthe linker Z is attached to the 6 position in Formula 1, to the 4position in Formula 2, to the 6 position in Formula 3, to the 6 positionin Formula 4, to the 4 position in Formula 5, to the 4 position inFormula 6, to the 6 position in Formula 7, and to the 6 position inFormula 8. These positions are indicated by arabic numerals in Formulas1 through 8.

[0258] The R₁ group substituting the non-aromatic rings in Formulas 1,3, 4, 7 and 8 is preferably alkyl, more preferably alkyl of 1 to 3carbons, and most preferably methyl. The R₁ group substituting thecyclopropane ring in Formulas 1, 2, 3 and 7 is preferably non-existent(p is 0), or is alkyl of 1 to 3 carbons, even more preferably methyl.

[0259] The X group in Formulas 1 and 5 is preferably O, and in Formula 2X is preferably O or NR.

[0260] The X₁ group in Formula 4 is preferably 1-imidazolyl, substituted1-imidazolyl, or NRR₆, where R₆ is preferably cyclopropyl orbranched-chain alkyl. The X₂ group in Formula 6 is preferably1-imidazolyl or substituted 1-imidazolyl.

[0261] The X₃ group in Formula 8 is preferably O or C═O.

[0262] The Y group is preferably H, lower alkyl of 1 to 3 carbons,cycloalkyl, lower alkyl substituted cycloalkyl, or halogen. Among these,H, Cl, and cyclopropyl are most preferred.

[0263] The Y₁ group of Formula 8 is preferably H, lower alkyl of 1 to 3carbons, cycloalkyl, or lower alkyl substituted cycloalkyl. Among theseH, ethyl and cyclopropyl are presently most preferred.

[0264] The most preferred compounds of the invention are disclosed inTables 2 through 9 with reference to Formulas 9 through 16. Thecompounds specifically shown in Tables 2 through 9 are carboxylic acids,but it should be understood that the C₁₋₃alkyl esters, methoxymethyl(OCH₂CH₃) esters and pharmaceutically acceptable salts of the acidsshown in these tables are also highly preferred.

[0265] It should also be apparent that the preferred compounds shown inTable 2 with reference to the more specific Formula 9 are within thescope of Formula 1.

[0266] Similarly, the preferred compounds shown in Table 3 withreference to the more specific Formula 10 are within the scope ofFormula 2;

[0267] the preferred compounds shown in Table 4 with reference to themore specific Formula 11 are within the scope of Formula 3;

[0268] the preferred compounds shown in Table 5 with reference to themore specific Formula 12 are within the scope of Formula 4;

[0269] the preferred compounds shown in Table 6 with reference to themore specific Formula 13 are within the scope of Formula 5;

[0270] the preferred compounds shown in Table 7 with reference to themore specific Formula 14 are within the scope of Formula 6;

[0271] the preferred compounds shown in Table 8 with reference to themore specific Formula 15 are within the scope of Formula 7, and

[0272] the preferred compounds shown in Table 9 with reference to themore specific Formula 16 are within the scope of Formula 8. TABLE 2Formula 9

Com- pound Position of No. X Y Z R₂ n (CH₂)_(n)COOH 40 O H —C≡C— H 0 442 O H —C≡C— H 1 4 44 O H —C≡C— F 0 4 48 O cyclopropyl —C≡C— H 1 4 50 Ocyclopropyl —C≡C— F 1 4 52 O cyclopropyl —C≡C— H 0 4 54 O cyclopropyl—C≡C— F 0 4 58 O cyclopropyl —CO—O— H 1 4 60 O cyclopropyl —CO—O— H 1 366 CH₃N H —C≡C— H 0 4

[0273] TABLE 3 Formula 10

Compound No. R₅ X R₃ n 110 n-propyl (n-propyl)N H 0 112 benzyl NH H 0114 benzyl (n-benzyl)N H 0 108 n-propyl NH H 0 116 benzyl methylN H 0 77benzyl O H 0 78 benzyl O H 1 70 methyl O H 1 69 methyl O H 0 73isopropyl O H 0 74 isopropyl O H 1 82 benzyl O methyl 1 81 benzyl Omethyl 0 89 (CH₃)₃C—CH₂— O methyl 0 90 (CH₃)₃C—CH₂— O methyl 1 94 benzylO ethyl 1 93 benzyl O ethyl 0 86 isopropyl O methyl 1 85 isopropyl Omethyl 0 105 ethyl O t-butyl 0 106 ethyl O t-butyl 1 98 isopropyl Oethyl 1

[0274] TABLE 4 Formula 11

Compound No. R₂ 22 F 24 H

[0275] TABLE 5 Formula 12

Compound No. X₁ R₂ n  3 methyl,cyclopropyl-N H 0  8 methyl,cyclopropyl-NH 1 13 methyl,cyclopropyl-N F 0 18 methyl,cyclopropyl-N F 1 139 1-imidazolyl H 0 137  1-imidazolyl H 1 26 methyl,isopropyl-N H 0

[0276] TABLE 6 Formula 13

Compound No. R₂ R₇ Y R₃ 143 H methyl t-butyl t-butyl 145 F methylt-butyl t-butyl

[0277] TABLE 7 Formula 14

Compound No. X₂ R₃ n 119 1-imidazolyl methyl 0 121 1-imidazolyl methyl 1127 1-imidazolyl iso-propyl 1 126 1-imidazolyl iso-propyl 0 134ethyl,cyclopropyl-N iso-propyl 0 130 ethyl,cyclopropyl-N methyl 0 131ethyl,cyclopropyl-N methyl 1 141 (1-methyl)cyclopropyl-oxy iso-propyl 1

[0278] TABLE 8 Formula 15

Compound No. R R₂ n 62 H H 0 63 Me H 1

[0279] TABLE 9 Formula 16

Compound No. X₃ Y₁ R₃ Z R₂ n 28 O H methyl —C≡C— H 1 30 O H methyl —C≡C—F 0  5 CO H H —C≡C— H 1 10 CO H H —C≡C— F 0 36 O cyclopropyl methyl—C≡C— H 1 38 O cyclopropyl methyl —C≡C— F 1 46 O H methyl —CO—O— H 1 20CO H H —CO—O— H 1 32 O H methyl —C≡C— F 1 56 O ethyl methyl —C≡C— H 1 34O cyclopropyl methyl —C≡C— H 0 15 CO H H —C≡C— F 1

[0280] The compounds of the invention can be synthesized by applying thegeneral synthetic methodology described above, and by such modificationsof the hereinafter described specific synthetic routes which will becomereadily apparent to the practicing synthetic organic chemist in light ofthis disclosure and in view of general knowledge available in the art.The hereinafter disclosed specific reaction schemes are directed to thesynthesis of exemplary and preferred compounds of the invention. Whereaseach of the specific and exemplary synthetic routes shown in theseschemes may describe specific compounds of the invention only within thescope of one or two of the general Formulas 1 through 8, the syntheticprocesses and methods used therein are adaptable within the skill of thepracticing organic chemist and can be used with such adaptation for thesynthesis of compounds of the invention which are not specificallydescribed herein as examples.

[0281] Reaction Scheme 1 discloses a presently preferred synthetic routeto certain intermediates or reagents having the general formulaX₄—A(R₂)—CH₂)_(n)—COOR₈, where the symbol A represents a di-, ortri-substituted phenyl moiety. These intermediates are utilized in thesynthesis of the compounds of the invention.

[0282] Reaction Scheme 2 discloses presently preferred synthetic routesto obtain exemplary and preferred tetrahydronaphthalenone compounds ofthe invention within the scope of Formula 8 where the symbol X₃represents a C═O group, Z represents an ethynyl moiety or a —COO—(ester) function, and A is a substituted phenyl moiety.

[0283] Reaction Scheme 3 discloses presently preferred synthetic routesto obtain exemplary and preferred tetrahydronaphthalene compounds of theinvention within the scope of Formula 4 where X₁ represents a dialkylsubstituted nitrogen, Z is an ethynyl moiety and A is a substitutedphenyl moiety.

[0284] Reaction Scheme 4 discloses presently preferred synthetic routesto obtain exemplary and preferred isoquinoline compounds of theinvention within the scope of Formula 3 where the symbol Y representshydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

[0285] Reaction Scheme 5 discloses presently preferred synthetic routesto obtain exemplary and preferred chroman compounds of the inventionwithin the scope of Formula 8 where the symbol Y₁ represents hydrogen, Zis an ethynyl moiety or an ester (COO) function, and A is a substitutedphenyl moiety.

[0286] Reaction Scheme 6 discloses presently preferred synthetic routesto obtain other exemplary and preferred chroman compounds of theinvention within the scope of Formula 8 where the symbol Y₁ represents acyclopropyl group, Z is an ethynyl moiety and A is a substituted phenylmoiety.

[0287] Reaction Scheme 7 discloses presently preferred synthetic routesto obtain exemplary and preferred chroman compounds of the inventionwithin the scope of Formula 1 where the symbol X represents oxygen (O),Y represents hydrogen, Z is an ethynyl moiety and A is a substitutedphenyl moiety.

[0288] Reaction Scheme 8 discloses presently preferred synthetic routesto obtain exemplary and preferred chroman compounds of the inventionwithin the scope of Formula 1 where the symbol X represents oxygen (O),Y represents hydrogen, Z is an ethynyl moiety and A is a substitutedphenyl moiety.

[0289] Reaction Scheme 9 discloses presently preferred synthetic routesto obtain exemplary and preferred tetrahydroquinoline compounds of theinvention within the scope of Formula 1 where the symbol X represents analkyl substituted nitrogen (alkyl-N), Y represents hydrogen, Z is anethynyl moiety and A is a substituted phenyl moiety.

[0290] Reaction Schemes 10 and 11 disclose presently preferred syntheticroutes to obtain exemplary and preferred phenyl compounds of theinvention within the scope of Formula 2 where the symbol X representsoxygen (O), R₅ is alkyl or benzyl, Z is an ethynyl moiety and A is asubstituted phenyl moiety.

[0291] Reaction Scheme 12 discloses presently preferred synthetic routesto obtain exemplary and preferred phenyl compounds of the inventionwithin the scope of Formula 2 where the symbol R₅—X represents an alkyl,dialkyl, benzyl or dibenzyl substituted nitrogen, Z is an ethynyl moietyand A is a substituted phenyl moiety.

[0292] Reaction Schemes 13 and 14 disclose presently preferred syntheticroutes to obtain exemplary and preferred phenyl compounds of theinvention within the scope of Formula 6 where the symbol X₂ represents a(1-imidazolyl) moiety, Z is an ethynyl moiety and A is a substitutedphenyl moiety.

[0293] Reaction Scheme 15 disclose presently preferred synthetic routesto obtain exemplary and preferred phenyl compounds of the inventionwithin the scope of Formula 6 where X₂ represents an alkyl andcyclopropyl substituted nitrogen (X₂=(alkyl,cycloalkyl)N), Y representshydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.

[0294] Reaction Scheme 16 discloses presently preferred synthetic routesto obtain exemplary and preferred tetrahydronaphthalene compounds of theinvention within the scope of Formula 4 where the symbol X₁ represents a(1-imidazolyl) moiety, Y represents hydrogen, Z is an ethynyl moiety andA is a substituted phenyl moiety.

[0295] Reaction Scheme 17 discloses presently preferred synthetic routesto obtain exemplary and preferred phenyl compounds of the inventionwithin the scope of Formula 6 where the symbol X₂ represents a1-methyl-cyclopropoxy moiety, Y represents hydrogen, Z is an ethynylmoiety and A is a substituted phenyl moiety.

[0296] Reaction Scheme 18 discloses presently preferred synthetic routesto obtain exemplary and preferred phenyl compounds of the inventionwithin the scope of Formula 5 where the symbol X represents oxygen (O),Y represents a tertiary-butyl group, Z is an ethynyl moiety and A is asubstituted phenyl moiety.

SPECIFIC EXAMPLES 4-Hydroxy Phenyl Acetic Acid-t-butyl Ester (Reagent E)

[0297] A stirred suspension of 4-hydroxy-phenyl acetic acid (0.152 g, 1mmol) in anhydrous toluene (5 mL) was heated at 80° C. and N,N-dimethylformamide-di-t-butyl acetal (1 mL, 4.17 mmol) was added when thesolution became homogenous. After 0.5 h, the reaction mixture was cooledto ambient temperature and the volatiles were distilled off in vacuo.The residue was diluted with water and extracted with diethyl ether(×2). The combined organic extract was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford an oil which wassubjected to flash column chromatography over silica gel (230-400 mesh)using 16% ethyl acetate in hexane as the eluent to afford the titlecompound as a solid (0.11 g, 56%).

[0298]¹H-NMR (300 MHz, CDCl₃): δ1.44(s, 9H), 3.45(s, 2H), 6.55(s, 1H),6.69(d, J=8.8 Hz, 2H), 7.06(d, J=8.5 Hz, 2H).

3-Hydroxy Phenyl Acetic Acid-t-butyl Ester (Reagent F)

[0299] A stirred suspension of 3-hydroxy-phenyl acetic acid (1.52 g, 10mmol) in anhydrous toluene (20 mL) was heated at 80° C. and N,N-dimethylformamide-di-t-butyl acetal (9.6 mL, 40 mmol) was added when thesolution became homogenous. After 0.5 h, the reaction mixture was cooledto ambient temperature and the volatiles were distilled off in vacuo. Thresidue was diluted with water and extracted with diethyl ether (×2).The combined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford an oil which was subjected toflash column chromatography over silica gel (230-400 mesh) using 16%ethyl acetate in hexane as the eluent to afford the title compound as asolid (1.17 g, 56%).

[0300]¹H-NMR (300 MHz, CDCl₃): δ1.47(s, 9H), 3.49(s, 2H), 6.30(s, 1H),6.70-6.79 (m, 2H), 6.81(d, J=7.6 Hz, 1H), 7.16(t, J=7.7 Hz, 1H).

Methyl-2-fluoro-4-iodo Benzoate (Reagent G)

[0301] A solution of 2-fluoro-4-iodo toluene (5 g, 26.6 mmol) inpyridine (2 mL) and water (20 mL) was treated with potassiumpermanganate (16.6 g, 105 mmol) and heated at 150° C. overnight. Thereaction mixture was then cooled to room temperature and filtered andthe filtrate was extracted with hexane. The aqueous phase was acidifiedwith 10% hydrochloric acid and extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo. The residue was dissolved in 20 mL of methanol, treated withconcentrated sulfuric acid (1 mL) and refluxed overnight. The volatileswere distilled off in vacuo and the residue was dissolved in diethylether, washed with brine, dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to an oil. Flash column chromatography oversilica gel (230-400 mesh) using 10% ethyl acetate in hexane as theeluent afforded the title compound as an oil (0.26 g, 5%).

[0302]¹H NMR (300 MHz, CDCl₃): δ7.60 (m, 4H), 3.93 (s, 3H).

Ethyl-2-fluoro-4-hydroxy Benzoate (Reagent I)

[0303] A solution of 2-fluoro-4-hydroxy benzoic acid (Intermediate 4, 3g, 19.2 mmol) in ethanol (65 mL) and benzene (90 mL) was treated withconcentrated sulfuric acid (1.5 mL) and heated at reflux overnight usinga Dean-Stark water trap. The volatiles were distilled off in vacuo andthe residue was diluted with water and diethyl ether. The phases wereseparated and the organic phase was washed with saturated aqueous sodiumbicarbonate (×1), water (×1) and brine (×1), dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titlecompound as a solid (3.07 g, 86%).

[0304]¹H-NMR (300 MHz, CD₃COCD₃): δ1.34 (t, J=7.1 Hz, 3H), 4.32 (q,J=7.1 Hz, 2H), 6.66(dd, J=2.6, 10.9 Hz, 1H), 6.76 (dd, J=2.3, 8.5 Hz,1H), 7.83(d, J=8.4 Hz, 1H), 9.91 (s, 1H).

Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6)

[0305] A stirred, cooled (ice bath) solution ofethyl-2-fluoro-4-hydroxy-benzoate (Intermediate 5, 0.368 g, 2 mmol) and2,6-di-tert-butyl-4-methyl-pyridine (0.81 g, 8 mmol) in 8 mL ofdichloromethane was treated with trifluoromethanesulfonic anhydride (0.1g, 4 mmol). The reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was subjected toflash column chromatography over silica gel (230-400 mesh) using 5-10%ethyl acetate in hexane as the eluent to afford the title compound (0.53g, 85%).

[0306]¹H-NMR (300 MHz, CDCl₃): δ1.41 (t, J=7.3 Hz, 3H), 4.42 (q, J=7.1Hz, 2H), 7.12-7.20(m, 2H), 8.08(t, J=8.3 Hz, 1H).

Ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate (Intermediate 7)

[0307] A solution ofethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6,1.82 g, 6 mmol) in triethyl amine (12 mL) and anhydrous tetrahydrofuran(30 mL) was treated with copper(I)iodide (0.12 g, 0.6 mmol) and spargedwith argon. Dichlorobis(triphenylphosphine)palladium(II) (0.43 g, 0.6mmol) was added followed by (trimethylsilyl)acetylene (3.6 mL, 24 mmol)and the resulting reaction mixture was heated at 70° C. overnight. Itwas then cooled to ambient temperature, diluted with diethyl ether andfiltered over a bed of celite. The filtrate was evaporated in vacuo toan oil which was subjected to flash column chromatography over silicagel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent toafford the title compound as an orange oil (1.5 g, quantitative).

[0308]¹H-NMR (300 MHz, CDCl₃): δ0.011 (s, 9H), 1.13(t, J=7.1 Hz, 3H),4.13 (q, J=7.1 Hz, 2H), 6.93-7.02(m, 2H), 7.07 (s, 1H), 7.61(t, J=7.9Hz, 1H).

Ethyl-4-ethynyl-2-fluoro Benzoate (Reagent D)

[0309] A solution of ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate(Intermediate 7, 1.5 g, 6 mmol) in ethanol (16 mL) was treated withpotassium carbonate (1.485 g, 10.74 mmol) and stirred overnight at roomtemperature. The reaction mixture was then diluted with water andextracted with diethyl ether (×2). The combined organic phase was driedover anhydrous magnesium sulfate, filtered and evaporated in vacuo toafford an orange oil. Flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent affordedthe title compound (1 g, 86%).

[0310]¹H-NMR (300 MHz, CDCl₃): δ1.39 (t, J=7.1 Hz, 3H), 3.26 (s, 1H),4.39 (q, J=7.1 Hz, 2H), 7.22-7.33 (m, 2H), 7.88(t, J=7.7 Hz, 1H).

Methyl-4-iodo-phenyl Acetate (Reagent B)

[0311] A solution of 4-iodo phenyl acetic acid (5 g, 19 mmol) inmethanol was treated with concentrated sulfuric acid (0.5 mL) andrefluxed overnight. The volatiles were distilled off in vacuo and theresidue was dissolved in ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent to affordthe title compound as a clear oil (5 g, 95%).

[0312]¹H NMR (300 MHz, CDCl₃): δ7.63 (d, 2H, J=8.5 Hz), 7.01 (d, 2H,J=8.0 Hz), 3.67 (s, 3H), 3.55 (s, 2H).

2-Fluoro-4-iodo-phenyl Acetonitrile (Intermediate 2)

[0313] A solution of 2-fluoro-4-iodo-benzyl bromide (Intermediate 1,2.56 g, 8.15 mmol) in ethanol (55 mL and water (10 mL) was treated withsodium cyanide (2.15 g, 43.86 mmol) and refluxed for 0.5 h. Thevolatiles were distilled off in vacuo and the residue was diluted withwater and extracted with diethyl ether (×2). The combined organicextract was washed with water (×1) and brine (×1), dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford the titlecompound as a pale yellow solid (2.05 g, 96%).

[0314]¹H-NMR (300 MHz, CDCl₃): δ3.71(s, 3H), 7.16(t, J=8.2 Hz, 1H),7.45(dd, J=1.7, 9.1 Hz, 1H), 7.51(dd, J=1.5, 8.2 Hz, 1H).

2-Fluoro-4-iodo-phenyl Acetic Acid (Intermediate 3)

[0315] A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate2, 2.05 g, 7.83 mmol) in ethanol (50 mL and water (15 mL) was treatedwith potassium hydroxide (3.4 g, 60.7 mmol) and refluxed for 4 h. Thevolatiles were distilled off in vacuo and the residue was diluted withwater and poured into cold, dilute hydrochloric acid and theprecipitated solid was filtered. The solid was dissolved in diethylether, and the organic solution was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo to afford the title compound apale yellow solid (1.75 g, 79%).

[0316]¹H-NMR (300 MHz, CDCl₃): δ3.64 (s, 2H), 6.98(t, J=7.9 Hz, 1H),7.25-7.46 (m, 2H), 9.60-10.40(br s, 1H).

Ethyl-2-fluoro-4-iodo-phenyl Acetate (Reagent C)

[0317] A solution of 2-fluoro-iodo-phenyl acetic acid (Intermediate 3,1.75 g, 6.22 mmol) in ethanol (50 mL) and benzene (100 mL) was treatedwith concentrated sulfuric acid (1.4 mL) and heated at reflux overnightusing a Dean-Stark water trap. The volatiles were distilled off in vacuoand the residue was diluted with water and diethyl ether. The phaseswere separated and the organic phase was washed with saturated aqueoussodium bicarbonate (×1), water (×1) and brine (×1), dried over anhydrousmagnesium sulfate, filtered and evaporated in vacuo to afford an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using 5%-10% ethyl acetate in hexane as the eluent toafford the title compound as a pale yellow solid (1.4 g, 73%).

[0318]¹H-NMR (300 MHz, CDCl₃): δ1.25 (t, J=7.1 Hz, 3H), 3.60 (s, 2H),4.16 (q, J=7.1 Hz, 2H), 6.99(t, J=8.0 Hz, 1H), 7.39-7.44(m, 2H).

Methyl-2-fluoro-4-iodo-phenyl Acetate (Reagent H)

[0319] A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate2, 3 g, 11.45 mmol) in methanol (50 mL) and benzene (50 mL) was treatedwith p-toluene sulfonic acid (2.5 g, 13.15 mmol) and heated at refluxovernight using a Dean-Stark water trap. The volatiles were distilledoff in vacuo and the residue was diluted with water and diethyl ether.The phases were separated and the organic phase was washed withsaturated aqueous sodium bicarbonate (×1), water (×1) and brine (×1),dried over anhydrous magnesium sulfate, filtered and evaporated in vacuoto afford an oil which was subjected to flash column chromatography oversilica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluentto afford the title compound as a colorless oil (2.7 g, 80%).

[0320]¹H-NMR (300 MHz, CDCl₃): δ3.62 (s, 2H), 3.70 (s, 3H), 6.99(t,J=7.9 Hz, 1H), 7.39-7.45(m, 2H).

General Procedure A:7-Methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 8)

[0321] A stirred, cooled (−40° C.) solution of titanium tetrachloride inanhydrous dichloromethane (1M, 20 mL) under argon, was treated with asolution of dimethyl zinc (2M, 40 mL) in toluene. After 0.5 h, asolution of 7-methoxy-1-tetralone (1.76 g, 10 mmol) in anhydrousdichloromethane (5 mL) was cannulated into the reaction mixture and theresulting solution was allowed to warm to ambient temperature andstirred overnight. The reaction mixture was then cooled to −40° C. andcautiously quenched with methanol (11 mL). It was diluted withdichloromethane and saturated aqueous ammonium chloride solution. Thephases were separated and the aqueous phase was extracted withdichloromethane (×2 mL). The combined organic phase was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to the titlecompound (1.75 g, 92%) as an oil.

[0322]¹H-NMR (300 MHz, CDCl₃): δ1.33(s, 6H), 1.67-1.71(m, 2H),1.79-1.90(m, 2H), 2.75(t, J=6.2 Hz, 2H), 3.83(s, 3H), 6.72(dd, J=2.6,8.3 Hz, 1H), 6.93(d, J=2.6 Hz, 1H), 7.02(d, J=8.3 Hz, 1H).

General Procedure B:6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate9)

[0323] A solution of7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 8,1.65 g, 8.7 mmol) in 7.5 mL of glacial acetic acid was cooled to 0° C.and treated with a solution of chromium trioxide (2 g, 20 mmol) in 8 mLof acetic acid and 7 mL of water. The reaction mixture was then allowedto warm to ambient temperature and stirred overnight. It was dilutedwith water and extracted with diethyl ether (×2). The combined organicphase was washed with water (×1), saturated aqueous sodium bicarbonate(×1) and brine (×1), dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to afford the title compound (1.64 g, 93%) as ayellow oil.

[0324]¹H-NMR (300 MHz, CDCl₃): δ1.34(s, 6H), 1.96(t, J=7.1 Hz, 2H),2.64(t, J=7.1 Hz, 2H), 3.83(s, 3H), 6.77(dd, J=2.6, 8.7 Hz, 1H), 6.83(d,J=2.5 Hz, 1H), 7.98(d, J=8.7 Hz, 1H).

6-Hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate10)

[0325] A stirred, cooled (−78° C.) solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate9, 0.8, 3 mmol) under argon was treated with a 1M solution of borontribromide (10 mL). The reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was cooled to−78° C., quenched and diluted with saturated aqueous sodium bicarbonatesolution and the aqueous phase was extracted with dichloromethane (×2).The combined organic phase was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to an oil. Flash column chromatographyover silica gel (230-400 mesh) using 30% ethyl acetate in hexane as theeluent afforded the title compound (0.3 g, 52%) as a yellow viscous oil.

[0326]¹H-NMR (300 MHz, CDCl₃): δ1.33(s, 6H), 1.97(t, J=6.8 Hz, 2H),2.71(t, J=6.7 Hz, 2H), 6.81(dd, J=2.3, 8.5 Hz, 1H), 6.94(d, J=2.3 Hz,1H), 7.98(d, J=8.7 Hz, 1H), 9.35(s, 1H).

General Procedure C:4,4-Dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11)

[0327] A stirred, cooled (0° C.) solution of6-hydroxy-4,4-dimethyl-1,2,3,4-terahydronaphthalene-1-one (Intermediate10, 0.3 g, 1.6 mmol) in anhydrous dichloromethane (10 mL) was treatedwith 4-(dimethylamino)pyridine (0.36 g, 3.27 mmol) followed by2-[N,N′-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (0.79 g, 2mmol). After stirring at ambient temperature for 0.75 h, the reactionmixture was diluted with dichloromethane and washed with water (×1). Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to an oil. Flash column chromatography over silicagel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluentafforded the title compound (0.462 g, 90%) as an off-white solid.

[0328]¹H-NMR (300 MHz, CDCl₃): δ1.36(s, 6H), 2.01(t, J=6.8 Hz, 2H),2.70(t, J=6.7 Hz, 2H), 7.15(dd, J=2.5, 8.7 Hz, 1H), 7.28(d, J=2.4 Hz,1H), 8.06(d, J=8.7 Hz, 1H).

General Procedure D:4,4-Dimethyl-6-trimethylsilanyl-ethynyl-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 12)

[0329] A solution of4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11, 0.46 g, 1.43 mmol) in triethyl amine (3 mL) andanhydrous tetrahydrofuran (8 mL) was treated with copper(I)iodide (0.1g, 0.53 mmol) and sparged with argon for 5 minutes. Trimethylsilylacetylene (0.85 mL, 6 mmol) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol). Theresulting reaction mixture was heated at 70° C. for 17 h. It was thencooled to ambient temperature, diluted with diethyl ether and filteredover a bed of celite. The filtrate was evaporated vacuo to an oil whichwas subjected to flash column chromatography over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent to afford the titlecompound (0.28 g, 72%).

[0330]¹H-NMR (300 MHz, CDCl₃): δ0.26(s, 9H), 1.36(s, 6H), 1.99(t, J=6.8Hz, 2H), 2.69(t, J=6.7 Hz, 2H), 7.35(dd, J=1.7, 8.2 Hz, 1H), 7.49(unresolved d, 1H), 7.93(d, J=8.1 Hz, 1H).

General Procedure E:6-Ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate13)

[0331] A solution of4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 12, 0.28 g, 1.03 mmol) in methanol (10 mL) was treatedwith potassium carbonate (0.74 g, 5.35 mmol) and stirred at ambienttemperature for 4 h. The volatiles were distilled off in vacuo and theresidue was diluted with water and extracted with diethyl ether (×2).The combined organic extract was dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound (0.19 g,89%) as an oil that solidified on standing.

[0332]¹H-NMR (300 MHz, CDCl₃): δ1.33(s, 6H), 1.96(t, J=6.8 Hz, 2H),2.67(t, J=6.8 Hz, 2H), 3.25(S, 1H), 7.33(dd, J=1.5, 8.1 Hz, 1H), 7.49(d, J=1.5 Hz, 1H), 7.13(d, J=8.1 Hz, 1H).

General Procedure F:4-(8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-benzoicAcid Ethyl Ester (Intermediate 14)

[0333] A solution of6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate13, 0.23 g, 1.1 mmol) and ethyl-4-iodo benzoate (Reagent A, 0.36 g, 1.3mmol) in triethyl amine (7 mL) and anhydrous tetrahydrofuran (3 mL) wastreated with copper(I)iodide (0.114 g, 0.6 mmol) and sparged with argonfor 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g,0.33 mmol) was added and the reaction mixture was stirred overnight atroom temperature. It was diluted with diethyl ether and filtered over abed of celite. The filtrate was evaporated in vacuo to a brown oil thatwas subjected to flash column chromatography over silica gel (230-400mesh) using 6-7% ethyl acetate in hexane as the eluent to afford thetitle compound (0.29 g, 72%) as a pale brown solid.

[0334]¹H-NMR (300 MHz, CDCl₃): δ1.3(t, J=7.1 Hz, 3H), 1.37(s, 6H), 1.80(t, J=6.8 Hz, 2H), 2.69(t, J=6.8 Hz, 2H), 4.35(q, J=7.1 Hz, 2H),7.40(dd, J=1.5, 8.2 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.3 Hz,2H), 7.96(d, J=8.2 Hz, 1H), 7.99(d, J=8.5 Hz, 2H).

General Procedure G4-(5-Cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2yl-ethynyl)-benzoicAcid Ethyl Ester (Compound 1, General Formula 4)

[0335] A solution of4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoicacid ethyl ester (Intermediate 14, 0.14 g, 0.4 mmol) in 3 mL ofdichloromethane and 2 mL of acetonitrile was treated with cyclopropylamine (1 mL, 14.45 mmol). After 5 minutes, acetic acid (1 mL) was addedfollowed by sodium cyanoborohydride (0.13 g, 2 mmol). The reaction wasstirred overnight at ambient temperature. It was then diluted with waterand saturated aqueous sodium carbonate solution and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oil.Flash column chromatography over silica gel (230-400 mesh) using 20%ethyl acetate in hexane as the eluent afforded the title compound (0.1g, 62%) as a pale yellow solid.

[0336]¹H-NMR (300 MHz, CDCl₃): δ0.30-0.60(m, 4H), 1.28(s, 3H), 1.35 (s,3H), 1.30(t, J=7.1 Hz, 3H), 1.55-1.61(m, 1H), 1.83-2.05(m, 3H), 2.25(quintet, J=3.0 Hz, 1H), 3.80 (t, J=4.9 Hz, 1H), 4.39(q, J=7.1 Hz, 2H),7.27-7.36(m, 2H), 7.52 (s, 1H), 7.55(d, J=8.3 Hz, 2H), 8.03(d, J=8.5 Hz,2H).

General Procedure H4-[(5-Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoicacid ethyl ester (Compound 2, General Formula 4)

[0337] A solution of4-(5-cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoicacid ethyl ester (Compound 1, 0.064 g, 0.16 mmol) in acetone (2 mL) wastreated with potassium carbonate (0.6 g, 4.34 mmol) and methyl iodide (1mL, 16 mmol) and stirred overnight at ambient temperature. The volatileswere distilled off in vacuo and the residue was diluted with water andextracted with dichloromethane (×2). The combined organic extract wasdried over anhydrous sodium sulfate, filtered and evaporated in vacuo toafford the title compound (0.065 g, 99%).

[0338]¹H-NMR (300 MHz, CDCl₃): δ0.28-0.49 (m, 4H), 1.21(s, 3H), 1.26 (s,3H), 1.33 (t, J=7.1 Hz, 3H), 1.58-1.73 (m, 2H), 1.83-1.89 (m, 2H),2.02-2.08 (m, 1H), 2.06 (s, 3H), 3.88 (t, J=8.1 Hz, 1H), 4.32(q, J=7.1Hz, 2H), 7.20(d, J=7.8 Hz, 1H), 7.41 (s, 1H), 7.46 (d, J=7.8 Hz, 1H),7.52(d, J=8.4 Hz, 2H), 8.03(d, J=8.3 Hz, 2H).

General Procedure I:4-[(5-Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2yl-ethynyl]-benzoicAcid (Compound 3, General Formula 4)

[0339] A solution of4-[(5-cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoicacid ethyl ester (Compound 2, 0.065 g, 0.158 mmol) in ethanol (1 mL) andtetrahydrofuran (1 mL) was treated with 1M aqueous sodium hydroxidesolution (1 mL) and heated at 80° C. for 1 h. The volatiles weredistilled off in vacuo and the residue was diluted with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate(×2). The combined organic extract was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford a solid that waswashed with dichloromethane and dried to afford the title compound(0.029 g, 38%) as a white solid.

[0340]¹H-NMR (300 MHz, CD₃COCD₃): δ0.35-0.51(m, 4H), 1.26(s, 3H), 1.29(s, 3H), 1.60-1.82(m, 2H), 1.88-2.02(m, 2H), 2.02-2.15 (m, 1H), 2.10 (s,3H), 3.93 (t, J=8.0 Hz, 1H), 7.26(dd, J=1.5, 8.2 Hz, 1H), 7.51 (d, J=1.5Hz, 1H), 7.52(d, J=8.2 Hz, 1H), 7.62(d, J=8.5 Hz, 2H), 8.02(d, J=8.2 Hz,2H).

4-[(8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticAcid Methyl Ester (Compound 4, General Formula 8)

[0341] Following general procedure F and using6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate13, 0.312 g, 1.5 mmol), 4-iodo phenyl acetic acid methyl ester (ReagentB, 0.50 g, 1.8 mmol), triethyl amine (7 mL), anhydrous tetrahydrofuran(3 mL), copper(I)iodide (0.04 g, 0.2 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 16-20% ethyl acetate in hexane as the eluent, the title compoundwas obtained as a pale yellow solid (0.42 g, 76%).

[0342]¹H-NMR (300 MHz, CDCl₃): δ1.42(s, 6H), 2.04(t, J=6.7 Hz, 2H),2.74(t, J=6.7 Hz, 2H), 3.66(s, 2H), 3.71(s, 3H), 7.29 (d, J=8.2 Hz, 2H),7.43(dd, J=1.5, 7.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.57 (d, J=1.5 Hz,1H), 8.00(d, J=8.2 Hz, 1H).

General Procedure J:4-[(8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticAcid (Compound 5, General Formula 8)

[0343] A solution of4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-phenyl]-aceticacid methyl ester (Compound 4, 0.1 g, 0.28 mmol) in a mixture ofmethanol (2 mL), tetrahydrofuran (3.5 mL) and water (1.5 mL) was treatedwith lithium hydroxide monohydrate (0.11 g, 2.62 mmol) and the resultingreaction mixture was stirred at ambient temperature for 3 h. Thevolatiles were distilled off in vacuo and the residue was diluted withwater and dilute hydrochloric acid and extracted with ethyl acetate(×3). The combined organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford the title compoundas a pale yellow solid (0.088 g, 92%).

[0344]¹H-NMR (300 MHz, CDCl₃): δ1.41(s,6H), 2.02(t, J=6.7 Hz, 2H),2.74(t, J=6.8 Hz, 2H), 3.68(s, 2H), 7.28 (d, J=8.2 Hz, 2H), 7.42(dd,J=1.5, 8.2 Hz, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.56 (d, J=1.5 Hz, 1H),7.99(d, J=8.2 Hz, 1H).

4-[(5-(Cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticAcid Methyl Ester (Compound 6, General Formula 4)

[0345] Following general procedure G and using4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticacid methyl ester (Compound 4, 0.2 g, 0.54 mmol), dichloromethane (4mL), acetonitrile(2 mL), cyclopropyl amine(1 mL, 14.45 mmol), aceticacid (1 mL) and sodium cyanoborohydride (0.16 g, 2.54 mmol) followed byflash column chromatography over silica gel (230-400 mesh) using 30%ethyl acetate in hexane as the eluent the title compound was obtained asa pale yellow oil (0.22 g, 99%).

[0346]¹H-NMR (300 MHz, CDCl₃): δ0.38-0.60 (m, 4H), 1.26(s, 3H), 1.33(s,3H), 1.50-1.59(m, 1H), 1.79-2.10 (m, 3H), 2.25(m, 1H), 3.63(s, 2H),3.69(s, 3H), 3.79(t, J=4.8 Hz, 1H), 7.20-7.32 (m, 4H), 7.47(s, 1H),7.58(d, J=8.2 Hz, 2H).

4-[(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticAcid Methyl Ester (Compound 7, General Formula 4)

[0347] Following general procedure H and using4-[(5-(cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-phenyl]-aceticacid methyl ester (Compound 6, 0.15 g, 0.37 mmol), acetone (5 mL),potassium carbonate (1.1 g, 7.95 mmol) and methyl iodide (1 mL, 16mmol), the following work-up was used. The volatiles were distilled offin vacuo and the residue was diluted with water and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford thetitle compound (0.148 g, 97%).

[0348]¹H-NMR (300 MHz, CDCl₃): δ0.38-0.58(m, 4H), 1.27(s, 3H), 1.31 (s,3H), 1.68-1.81(m, 2H), 1.85-1.98(m, 2H), 2.08-2.15 (m, 1H), 2.12 (s,3H), 3.62(s, 2H), 3.69(s, 3H), 3.94 (t, J=7.9 Hz, 1H), 7.24(d, J=8.2 Hz,1H), 7.24 (d, J=8.2 Hz, 2H), 7.44-7.51(m, 4H).

4-[(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-aceticAcid (Compound 8, General Formula 4)

[0349] Following general procedure J and using4-[(5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-phenyl]-aceticacid methyl ester (Compound 7, 0.148 g, 0.357 mmol), methanol (2 mL),tetrahydrofuran (4 mL), water (1 mL) and lithium hydroxide monohydrate(0.25 g, 5.95 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 30-75% ethyl acetate in hexane as the eluent,the title compound was obtained as a white solid (0.08 g, 56%).

[0350]¹H-NMR (300 MHz, CDCl₃): δ0.52-0.54(m, 2H), 0.68-0.70(m, 2H),1.27(s, 3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H),2.19-2.24(m, 1H), 2.24(s, 3H), 3.60(s, 2H), 4.18(t, J=7.7 Hz, 1H),7.24(dd, J=1.5, 8.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz,1H), 7.47(s, 1H), 7.47(d, J=8.2 Hz, 2H), 10.37(br s, 1H).

2-Fluoro-4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl]benzoicAcid Ethyl Ester (Compound 9, General Formula 8)

[0351] A solution of4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11, 0.3 g, 0.9 mmol), copper(I)iodide (0.057 g, 0.3 mmol)and ethyl-2-fluoro-4-ethynyl-benzoate (Reagent D, 0.44 g, 2.27 mmol) intriethyl amine (2 mL) and tetrahydrofuran (3 mL) was sparged with argonfor 5 minutes and treated withdichlorobis(triphenylphosphine)palladium(II) (0.135 g, 0.192 mmol) andstirred at room temperature overnight and then refluxed for 2 h. It wasthen cooled to ambient temperature, diluted with diethyl ether andfiltered over a bed of celite. The filtrate was evaporated in vacuo toan oil which was subjected to flash column chromatography over silicagel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent toafford the title compound as a yellow solid (0.22 g, 67%).

[0352]¹H-NMR (300 MHz, CDCl₃): δ1.38 (t, J=7.0 Hz, 3H), 1.39(s, 6H),2.01(t, J=6.7 Hz, 2H), 2.71(t, J=6.7 Hz, 2H), 4.37(q, J=7 Hz, 2H),7.28(dd, J=0.9, 10 Hz, 1H), 7.34(dd, J=0.9, 8.2 Hz, 1H), 7.41 (dd,J=1.5, 8.2 Hz, 1H), 7.57(d, J=0.9 Hz), 7.90(t, J=7.9 Hz, 1H), 7.93 (d,J=7.9 Hz, 1H).

2-Fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl-ethynyl)-benzoicAcid (Compound 10, General Formula 8)

[0353] A solution of2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)benzoicacid ethyl ester (Compound 9, 0.1 g, 0.274 mmol) in ethanol(4 mL),methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 1M aqueoussodium hydroxide solution and heated at 70° C. for 1 h. The volatileswere distilled off in vacuo and the residue was diluted with water anddilute hydrochloric acid and extracted with ethyl acetate (×2). Thecombined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford a solid that wasrecrystallized from hot aqueous acetonitrile to afford the titlecompound (0.025 g, 27%).

[0354]¹H-NMR (300 MHz, CDCl₃): δ1.43(s, 6H), 2.05(t, J=6.9 Hz, 2H),2.76(t, J=6.9 Hz, 2H), 7.26-7.47(m, 3H), 7.60(d, J=1.1 Hz, 1H),7.99-8.05(m, 2H).

4-[5-(Cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluoro-benzoicAcid Ethyl Ester (Compound 11, General Formula 4)

[0355] Following general procedure G and using2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoicacid ethyl ester (Compound 9, 0.132 g, 0.3 mmol), dichloromethane (4mL), acetonitrile(2 mL), cyclopropyl amine (1 mL, 14.45 mmol), aceticacid (1 mL)and sodium cyanoborohydride (0.18 g, 2.86 mmol) followed byflash column chromatography over silica gel (230-400 mesh) using 16-20%ethyl acetate in hexane as the eluent, the title compound was obtainedas a pale yellow oil (0.1 g, 82%).

[0356]¹H-NMR (300 MHz, CDCl₃): δ0.36-0.54 (m, 4H), 1.27(s, 3H), 1.33(s,3H), 1.40(t, J=7.0 Hz, 3H), 1.54-1.61(m, 2H), 1.82-2.05 (m, 2H), 2.26(m,1H), 3.79 (t, J=4.9 Hz, 1H), 4.39(q, J=7.1 Hz, 2H), 7.26-7.50(m, 4H),7.87(s, 1H), 7.92 (t, J=7.9 Hz, 1H).

4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluoroBenzoic Acid Ethyl Ester (Compound 12, General Formula 4)

[0357] Following general procedure H and using4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-benzoicacid ethyl ester (Compound 11, 0.1 g, 0.246 mmol), acetone (4 mL),potassium carbonate (0.917 g, 6.63 mmol) and methyl iodide (0.8 mL, 11mmol), the following work-up was used. The volatiles were distilled offin vacuo and the residue was diluted with water and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oil.Flash column chromatography over silica gel (230-400 mesh) using 8-10%ethyl acetate in hexane as the eluent afforded the title compound as apale yellow oil (0.102 g, 98%).

[0358]¹H-NMR (300 MHz, CDCl₃): δ0.39-0.62 (m, 4H), 1.29(s, 3H), 1.34(s,3H), 1.42(t, J=6.9 Hz, 3H), 1.65-1.82(m, 2H), 1.85-2.02 (m, 2H),2.02-2.10(m, 1H), 2.15(s, 3H), 3.97(t, J=7.7 Hz, 1H), 4.42(q, J=7.0 Hz,2H), 7.28-7.36 (m, 3H), 7.59(s, 1H), 7.55(d, J=7.9 Hz, 2H), 7.92 (t,J=7.5 Hz, 1H).

4-[5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluoroBenzoic Acid (Compound 13, General Formula 4)

[0359] Following general procedure I and using4-[(5-cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-benzoicacid ethyl ester (Compound 12, 0.102 g, 0.23 mmol), ethanol (4 mL) and1M aqueous sodium hydroxide solution (2 mL) followed by flash columnchromatography over silica gel (230-400 mesh) 30% ethyl acetate inhexane as the eluent, the title compound was obtained as an off-whitesolid (0.015 g, 16%).

[0360]¹H-NMR (300 MHz, CDCl₃): δ0.54-0.65 (m, 4H), 1.29 (s, 3H), 1.32(s, 3H), 1.68-1.83 (m, 2H), 1.97-2.05 (m, 2H), 2.18-2.25 (m, 1H), 2.25(s, 3H), 4.13 (t, J=6.7 Hz, 1H), 7.26-7.30 (m, 2H), 7.34 (dd, J=1.5, 7.9Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.95 (t, J=7.9Hz, 1H).

[2-Fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]aceticAcid Ethyl Ester (Compound 14, General Formula 8)

[0361] Following general procedure F and using6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-one(Intermediate 13, 0.298 g, 1.43 mmol), 2-fluoro-4-iodo phenyl aceticacid ethyl ester (Reagent C, 0.44 g, 1.43 mmol), triethyl amine(Intermediate 13, 3 mL), anhydrous tetrahydrofuran (7 mL),copper(I)iodide (0.04 g, 0.2 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 14-16% ethyl acetate in hexane as the eluent, the title compoundwas obtained as an oil (0.43 g, 77%).

[0362]¹H-NMR (300 MHz, CDCl₃): δ1.26(t, J=7.2 Hz, 3H), 1.41(s, 6H),2.04(t, J=6.7 Hz, 2H), 2.74(t, J=6.7 Hz, 2H), 3.68(s, 2H), 4.18(q, J=7.1Hz, 2H), 7.23-7.57(m, 4H), 7.59 (d, J=1.5 Hz, 1H), 7.99(d, J=7.9 Hz,1H).

[2-Fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)phenyl]-aceticAcid (Compound 15, General Formula 8)

[0363] Following general procedure J and using[2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]aceticacid methyl ester (Compound 14, 0.18 g, 0.48 mmol), methanol (4 mL),tetrahydrofuran (8 mL), water (2 mL) and lithium hydroxide monohydrate(0.2 g, 4.76 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 50-100% ethyl acetate in hexane as the eluent,the title compound was obtained as a dirty white solid (0.068 g, 41%).

[0364]¹H-NMR (300 MHz, CDCl₃): δ1.41(s, 6H), 2.03(t, J=6.7 Hz, 2H),2.74(t, J=6.8 Hz, 2H), 3.73(s, 2H), 7.24-7.32(m, 3H), 7.42(dd, J=1.5,7.9 Hz, 1H), 7.56 (s, 1H), 7.99(d, J=7.9 Hz, 1H), 9.40-10.00 (br s, 1H).

[4-(5-(Cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]Acetic Acid Ethyl Ester (Compound 16, General Formula 4)

[0365] Following general procedure G and using[2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]aceticacid ethyl ester (Compound 14, 0.258 g, 0.68 mmol), dichloromethane (4mL), acetonitrile (2 mL), cyclopropyl amine (1 mL, 14.45 mmol), aceticacid (1 mL) and sodium cyanoborohydride (0.266 g, 4.23 mmol) followed byflash column chromatography over silica gel (230-400 mesh) using16-20-25% ethyl acetate in hexane as the eluent, the title compound wasobtained as a pale yellow oil (0.21 g, 73%).

[0366]¹H-NMR (300 MHz, CDCl₃): δ0.35-0.54 (m, 4H), 1.25(t, J=7.1 Hz,3H), 1.26(s, 3H), 1.32(s, 3H), 1.53-1.64(m, 1H), 1.82-2.05 (m, 3H),2.21-2.28(m, 1H), 3.65(s, 2H), 3.78(t, J=5.0 Hz, 1H), 4.17(q, J=7.1 Hz,2H), 7.19-7.41 (m, 5H), 7.47(d, J=1.5 Hz, 1H).

[4-(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]-aceticAcid Ethyl Ester (Compound 17, General Formula 8)

[0367] Following general procedure H and using[4-((5-cyclopropyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-2-fluoro-phenyl]aceticacid ethyl ester (Compound 16, 0.21 g, 0.5 mmol), acetone (5 mL),potassium carbonate (1.13 g, 8.17 mmol) and methyl iodide (0.5 mL, 8mmol), the following work-up was used. The volatiles were distilled offin vacuo and the residue was diluted with water and extracted withdichloromethane (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford anoil. Flash column chromatography over silica gel (230-400 mesh) using 8%ethyl acetate in hexane as the eluent afforded the title compound (0.15g, 69%).

[0368]¹H-NMR (300 MHz, CDCl₃): δ0.39-0.53(m, 4H), 1.27(s, 3H), 1.31 (s,3H), 1.66-1.81(m, 2H), 1.89-2.05(m, 2H), 2.08-2.13 (m, 1H), 2.13 (s,3H), 3.62(s, 2H), 3.94 (t, J=8.0 Hz, 1H), 4.16(q, J=7.1 Hz, 2H),7.20-7.29(m, 4H), 7.44(d, J=1.5 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H).

[4-(5-(Cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]-aceticAcid (Compound 18, General Formula 4)

[0369] Following general procedure J and using[4-(5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro-phenyl]-aceticacid ethyl ester (Compound 17, 0.025 g, 0.059 mmol), methanol (1 mL),tetrahydrofuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate(0.060 g, 1.43 mmol), the title compound was obtained as a white solid(0.023 g, 95%).

[0370]¹H-NMR (300 MHz, CDCl₃): δ0.52-0.54(m, 2H), 0.68-0.70(m, 2H),1.27(s, 3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H),2.19-2.24(m, 1H), 2.24(s, 3H), 3.60(s, 2H), 4.18(t, J=7.7 Hz, 1H),7.19-7.28(m, 4H), 7.45 (d, J=1.5 Hz, 1H), 7.49(d, J=8.2 Hz, 1H),8.80-9.20(br s, 1H).

General Procedure K:8,8-Dimethyl-5,6,7,8-tetrahydro-naphthalene-1-one-2-carboxylicAcid-4-(tert-butoxycarbonylmethyl)phenyl Ester Compound 19, GeneralFormula 8)

[0371] A solution of4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one(Intermediate 11, 0.14 g, 0.434 mmol), t-butyl-4-hydroxy-phenyl acetate(Reagent E, 0.14 g, 0.673 mmol), palladium acetate (0.054 g, 0.24 mmol)and 1,3-bis(diphenylphosphino)propane (0.082 g, 0.2 mmol) in a mixtureof dimethylsulfoxide (1 mL), 1,2-dichloroethane (1.5 mL) and triethylamine (1 mL) was heated at 70° C. under an atmosphere of carbon monoxideovernight. The volatiles were distilled of in vacuo and the residue wasdiluted with water and extracted with diethyl ether (×3). The combinedorganic extract was dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to an oil which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 15% ethyl acetate inhexane as the eluent to afford the title compound (0.11 g, 53%).

[0372]¹H-NMR (300 MHz, CDCl₃): δ1.44(s, 3H), 1.44(s, 9H), 1.46 (s, 3H),2.07(t, J=6.9 Hz, 2H), 2.76(t, J=6.8 Hz, 2H), 3.55(s, 2H), 7.17 (d,J=8.5 Hz, 2H), 7.35(d, J=8.5 Hz, 2H), 8.05-8.13(m, 2H), 8.25 (d, J=1.5Hz, 1H).

8,8-Dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylicAcid-4-(carboxymethyl)phenyl Ester (Compound 20, General Formula 8)

[0373] A solution of8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 19, 0.11 g, 0.229mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid(0.85 mL and stirred at ambient temperature for 2.5 h. The volatileswere distilled off in vacuo and the residue was diluted with water andextracted with ethyl acetate (×3). The combined organic phase was driedover anhydrous sodium sulfate, filtered and evaporated in vacuo toafford a solid which was subjected to flash column chromatography oversilica gel (230-400 mesh) using ethyl acetate as the eluent to affordthe title compound (0.024 g, 25%).

[0374]¹H-NMR (300 MHz, CDCl₃): δ1.46 (s, 6H), 2.08(t, J=6.7 Hz, 2H),2.80(t, J=6.7 Hz, 2H), 3.70(s, 2H), 7.20(d, J=8.5 Hz, 2H), 7.37(d, J=8.5Hz, 2H), 8.08(dd, J=1.4, 8.2 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.24 (d,J=1.2 Hz, 1H).

5-Methoxy-3,3-dimethyl-indane (Intermediate 15)

[0375] Following general procedure A and using titanium tetrachloride(5.5 mL, 50 mmol), anhydrous dichloromethane (80 mL), 2M solutiondimethyl zinc (50 mL) in toluene and a solution of6-methoxy-indane-1-one (4.05 g, 25 mmol) in dichloromethane (pb 10 ml)the title compound was obtained as an oil (3.13 g, 71%). ¹H-NMR (300MHz, CDC1₃): δ1.37(s,6H), 2.04(t,J=7.2Hz,2H), 2.94(t,J=7.2Hz, 2H),3.89(s,3H), 6.82(d,J=2.1Hz, 1H), 7.35(d,J=7.0Hz, 1H).

[0376] 5-Methoxy-3,3-dimethyl-indane-1-one (Intermediate 16)

[0377] Following general procedure B and using 5-mehtoxy-3,3-dimethylindane (Intermediate 15,3.13 g, 17.78 mmol) in 20 ml of acetic acid and20 ml of water the title compound was obtained as a viscous yellow oil(3.3 g, 97%). ¹H-NMR (300 MHz, CDC1₃): δ1.37(s,6H), 2.54(sm2H),3.87(s,3H), 6.86-6.87(m, 2H), 7.60(d,J=7.0Hz, 1H).

[0378]6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-1-one(Intermediatepb 17)

[0379] A solution of pb 5-methoxy-3,3-dimethyl-indane-1-one(Intermediate 16,3.3 g, 17.4 mmol) in benzene (50 ml) was trated withcincentrated sulfuric acid (10 ml) and heated to 60° C. Sodium azide(1.95 g, 30 mmol) was added in small portions and after the sddition wascomplete, the reaction mixture was heated futher for 4 h. It was thencooled, diluted with water and extracted with chloroform (x3). Thecombined organic phase was dried with water and extracted with choloform(x 3). The combined organic phase was dried over anhydrous magnesiumsulfate, filtered and evaporated in bacuo to afford the title compoundas a brown solid (3.5 g, quantitative by weight).

[0380]¹H-NMR (300 MHzm CDC1₃): δ1.31 ( sm 6H) , 3.28(s,2H), 3.83(s3H),6.78(d,J=2.6Hz, 1H), 6.82(ddmJ=2.6Hz, 8.5Hz, 1H), 8.02(d,J=

6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 18)

[0381] A solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-1-one(Intermediate 17, 3.5 g, 17 mmol) in 100 mL of anhydrous tetrahydrofuranwas treated with lithium aluminum hydride (1.3 g, 34.25 mmol) in smallportions and the resulting suspension was refluxed for 3 hours underargon. The reaction mixture was then cooled in an ice bath andcautiously quenched with saturated aqueous sodium sulfate solution andthe resulting slurry was filtered and the filter-cake washed well withethyl acetate. The filtrate and washings were evaporated in vacuo to abrown oil which was dissolved in chloroform, the solution was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound (3.2 g, ˜100%).

[0382]¹H-NMR (300 MHz, CDCl₃): δ1.27 (s, 6H), 2.22 (s, 1H), 2.84 (s,2H), 3.79 (s, 3H), 3.95 (s, 2H), 6.68(dd, J=2.4 Hz, 8.3 Hz,1H), 6.86(d,J=2.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H).

6-Methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 19)

[0383] A solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 18,3.2 g, 16.7 mmol) in anhydrous dichloromethane (40 mL) was treated withformic acid (1 mL, 26.5 mmol) followed1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9 g,20.34 mmol) and the resulting solution was stirred at ambienttemperature overnight. It was then diluted with chloroform and washedwith water (×1) and brine (×1), dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo to afford the title compound as palebrown viscous oil (3.26 g, 90%).

[0384]¹H-NMR (300 MHz, CDCl₃): δ1.28 (s, 6H), 3.32 (s, 0.7H), 3.54 (s,0.3H), 3.79(s, 3H), 4.54 (s, 0.3H), 4.66(s, 0.7H), 6.71(dd, J=2.6 Hz,8.2 Hz, 1H), 6.85-6.97(m, 1H), 7.02-7.27(m, 1H), 8.15(s, 0.7H), 8.34(s,0.3H), 8.40-8.80 (br s, 1H).

6-Hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 20)

[0385] A stirred, cooled (−78° C.) solution of6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 19, 3.26 g, 15 mmol) in anhydrous dichloromethane (15 mL)was treated with 1M solution of boron tribromide in dichloromethane (50mL) stirred at ambient temperature for 3 h. It was then cooled again to78° C. and quenched carefully with saturated aqueous sodium carbonatesolution, diluted with water and the aqueous phase was extracted withethyl acetate (×2). The combined organic extract was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford thetitle compound as a solid foam (3 g, 99%).

[0386]¹H-NMR (300 MHz, CDCl₃): δ1.23 (s, 6H), 3.31 (s, 0.7H), 3.54 (s,0.3H), 4.51 (s, 0.3H), 4.64 (s, 0.7H), 6.70-6.75(m, 1H), 6.84-6.90(m,2H), 7.50-7.80(br s, 1H), 8.12(s, 0.7H), 8.32(s, 0.3H).

2-Cyclopropyl-6-hydroxy-4,4-dimethyl -1,2,3,4-tetrahydro-isoquinoline(Intermediate 21)

[0387] A stirred, cooled (0° C.) solution of6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde(Intermediate 20, 2.3 g, 11.21 mmol) in anhydrous tetrahydrofuran (40mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL,28 mmol) followed by 3M solution of ethyl magnesium bromide in diethylether (18.7 mL) and the reaction mixture was then heated at 55° C.overnight. It was then cooled in an ice-bath, quenched with saturatedaqueous ammonium chloride solution and extracted with diethyl ether(×2). The combined organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford a yellow oily solid.Flash column chromatography over silica gel (230-400 mesh) using 10-20%ethyl acetate in hexane as the eluent afforded the title compound as apale yellow solid (1.55 g, 63%).

[0388]¹H-NMR (300 MHz, CD₃COCD₃): δ0.016-0.16(m, 4H), 0.847 (s, 6H),1.37 (m, 1H), 2.20(s, 2H), 3.25 (s, 2H), 6.22(dd, J=2.4, 8.2 Hz, 1H),6.41(d, J=2.6 Hz, 1H), 6.47(d, J=8.2 Hz, 1H), 7.62(s, 1H).

2-Cyclopropyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline(Intermediate 22)

[0389] Following general procedure C and using2-cyclopropyl-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 21, 1.5 g, 6.9 mmol) in anhydrous dichloromethane (30 mL),triethyl amine (1.5 mL, 10.39 mmol) and[N,N′-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (2.75 g, 7mmol) followed by flash column chromatography over silica gel (230-400mesh) using 8% ethyl acetate in hexane as the eluent the title compoundwas obtained (2.23 g, 92%) as oil.

[0390]¹H-NMR (300 MHz, CDCl₃): δ0.42-0.54(m, 4H), 1.25(s, 6H), 1.76(m,1H), 2.62(s, 2H), 3.74(s, 2H), 6.98(dd, J=2.3, 8.4 Hz, 1H), 7.16(d,J=8.2 Hz, 1H), 7.14(d, J=2.3 Hz, 1H).

Ethyl-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate(Intermediate 23)

[0391] Following general procedure K and using2-cyclopropyl-4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline(Intermediate 22, 1.6 g, 4.6 mmol), palladium acetate (0.127 g, 0.56mmol), 1,3-bis(diphenylphosphino)propane (0.160 g, 0.39 mmol),dimethylsulfoxide (2 mL), 1,2-dichloroethane (5 mL), triethyl amine (2mL), ethanol (5 mL) and an atmosphere of carbon monoxide followed byflash column chromatography over silica gel (230-400 mesh) using 10%ethyl acetate in hexane as the eluent the title compound was obtained asan oil (1 g, 79%).

[0392]¹H-NMR (300 MHz, CDCl₃): δ0.44-0.54(m, 4H), 1.27(s, 6H), 1.38 (t,J=7 Hz, 3H), 1.73(m, 1H), 2.62(s, 2H), 3.76(s, 2H), 4.35 (q, J=7.1 Hz,2H), 7.04(d, J=7.9 Hz, 1H), 7.74 (dd, J=1.7, 7.9 Hz, 1H), 7.97(d, J=1.8Hz, 1H).

2-Cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 24)

[0393] A stirred cooled (−78° C.)solution ofethyl-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Intermediate 23, 1 g, 3.66 mmol) inanhydrous dichloromethane (20 mL) under argon was treated with a 1Msolution of di-iso-butyl aluminum hydride in dichloromethane (10 mL) andthe reaction mixture was warmed to −20° C. over 1 h. It was thenquenched with saturated aqueous ammonium chloride solution and dilutedwith dichloromethane and filtered over a bed of celite. The phases wereseparated and the aqueous phase was extracted with dichloromethane (×1).The combined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford the title compound as aviscous oil (0.74 g, 87%).

[0394]¹H-NMR (300 MHz, CDCl₃): δ0.45-0.53(m, 4H), 1.25(s, 6H),1.72-1.82(m, 2H), 2.61(s, 2H), 3.73(s, 2H), 4.61 (d, J=5 Hz, 2H),6.98(d, J=7.9 Hz, 1H), 7.07 (dd, J=1.5, 7.6 Hz, 1H), 7.27(s, 1H).

2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde(Intermediate 25)

[0395] A solution of2-cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 24, 0.74 g, 3.2 mmol) in dichloromethane (10 mL) andacetonitrile (2.5 mL) was treated sequentially with 4A° molecular sievespowder (1.06 g), tetra-n-propyl ammonium perruthenate (0.050 g, 0.14mmol) and N-methyl morpholine N-oxide (1.1 g, 9.8 mmol). After stirringat ambient temperature for 0.5 h, it was diluted with 5 mL of hexane andsubjected to flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent to afford the titlecompound as an oil (0.27 g, 37%).

[0396]¹H-NMR (300 MHz, CDCl₃): δ0.44-0.56(m, 4H), 1.30(s, 6H), 1.79(m,1H), 2.66(s, 2H), 3.82(s, 2H), 7.17(d, J=7.9 Hz, 1H), 7.60 (dd, J=1.6,7.9 Hz, 1H), 7.82(d, J=1.8 Hz, 1H), 9.95 (s, 1H).

6-(2,2-Dibromo-vinyl)-2-cyclopropyl-4,4-dimethyl-1,2,34-tetrahydroisoquinoline (Intermediate 26)

[0397] A stirred, cooled (ice-bath) solution of triphenyl phosphine(0.53 g, 2 mmol) in anhydrous dichloromethane was treated with carbontetrabromide (0.35 g, 1 mmol) under argon. After 0.5 h, a solution of2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde(Intermediate 25, 0.13 g, 0.57 mmol) in dichloromethane (2 mL) wascannulated into the reaction mixture. After 1.5 h between 0° C. and 10°C., the reaction mixture was subjected to flash column chromatographyover silica gel (230-400 mesh) using 3-5% ethyl acetate in hexane as theeluent to afford the title compound as a viscous, pale yellow oil (0.18g, 82%).

[0398]¹H-NMR (300 MHz, CDCl₃): δ0.49-0.57(m, 4H), 1.31(s, 6H), 1.80(m,1H), 2.67(s, 2H), 3.77(s, 2H), 7.04(d, J=7.9 Hz, 1H), 7.29 (dd, J=1.7,7.9 Hz, 1H), 7.49 (s, 1H), 7.50(d, J=1.7 Hz, 1H).

2-Cyclopropyl-6-ethynyl-1.4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline(Intermediate 27)

[0399] A stirred, cooled (−78° C.) solution of6-(2,2-dibromo-vinyl)-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde(Intermediate 26, 0.18 g, 0.47 mmol) in tetrahydrofuran (2 mL) wastreated with 1.6M solution of n-butyl lithium (0.6 mL, 0.96 mmol) underargon. The reaction mixture was allowed to warm to −20° C. over 1.5 h,quenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether (×2). The combined organic phase was dried overanhydrous magnesium sulfate, filtered and evaporated in vacuo to affordthe title compound as an oil (0.1 g, 94%).

[0400]¹H-NMR (300 MHz, CDCl₃): δ0.47-0.55(m, 4H), 1.28(s, 6H), 1.77(m,1H), 2.63(s, 2H), 3.05(s, 1H), 3.67(s, 2H), 6.98(d, J=7.6 Hz, 1H), 7.26(dd, J=1.5, 7.9 Hz, 1H), 7.46(d, J=1.5 Hz, 1H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-2-fluoro-phenyl]-aceticAcid Ethyl Ester (Compound 21, General Formula 3)

[0401] Following general procedure F and using2-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, 0.571 mmol), 2-fluoro-4-iodo phenyl aceticacid ethyl ester (Reagent C, 0.16 g, 0.52 mmol), triethyl amine (0.8mL), anhydrous tetrahydrofuran (2 mL), copper(I)iodide (0.051 g, 0.27mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14mmol) followed by flash column chromatography over silica gel (230-400mesh) using 10% ethyl acetate in hexane as the eluent, 0.1 g of thetitle compound was obtained as an oil. It was further purified bypreparative normal phase HPLC on a partisil-10 silica column using 10%ethyl acetate in hexane as the mobile phase (0.055 g, 24%).

[0402]¹H-NMR (300 MHz, CDCl₃): δ0.42-0.51 (m, 4H), 1.26(t, J=7.3 Hz,3H), 1.27(s, 6H), 1.75(m, 1H), 2.61(s, 2H), 3.66(s, 2H), 3.74(s, 2H),4.18 (q, J=7.3 Hz, 2H), 6.97 (d, J=7.9 Hz, 1H), 7.20-7.29(m, 4H),7.45(d, J=1.5 Hz, 1H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-2-fluoro-phenyl]-aceticAcid (Compound 22, General Formula 3)

[0403] Following general procedure J and using[4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-aceticacid ethyl ester (Compound 21, 0.055 g, 0.135 mmol), methanol (2 mL),tetrahydrofuran (4 mL), water (1 mL) and lithium hydroxide monohydrate(0.117 g, 2.97 mmol) the title compound was obtained as a pale yellowsolid foam (0.040 g, 78%).

[0404]¹H-NMR (300 MHz, CDCl₃): δ0.52-0.65(m, 4H), 1.27(s, 6H), 1.84(m,1H), 2.71(s, 2H), 3.61(s, 2H), 3.85(s, 2H), 6.98(d, J=7.9 Hz, 1H), 7.06(t, J=7.6 Hz, 1H), 7.17-7.25(m, 3H), 7.43(d, J=1.2 Hz, 1H), 8.60-9.00(brs, 1H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-phenyl]-aceticAcid Methyl Ester (Compound 23, General Formula 3)

[0405] Following general procedure F and using2-cyclopropyl-4,4-dimethyl-6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, 0.571 mmol), 4-iodo phenyl acetic acid methylester (Reagent B, 0.16 g, 0.58 mmol), triethyl amine (0.5 mL), anhydroustetrahydrofuran (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, 0.05 g of the titlecompound was obtained as an oil. It was further purified by preparativenormal phase HPLC on a partisil-10 silica column using 10% ethyl acetatein hexane as the mobile phase (0.01 g, 6%).

[0406]¹H-NMR (300 MHz, CDCl₃): δ0.42-0.58(m, 4H), 1.29(m, 6H), 1.79(m,1H), 2.64(s, 2H), 3.67(s, 3H), 3.72(s, 2H), 3.77(s, 2H), 7.09 (d, J=7.9Hz, 1H), 7.28(dd, J=1.5, 7.9 Hz, 1H), 7.36 (d, J7.9 Hz, 2H), 7.50 (d,J=1.6 Hz, 1H), 7.51(d, J=7.9 Hz, 2H).

[4-(2-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-phenyl]-aceticAcid (Compound 24, General Formula 3)

[0407] Following general procedure J and using[4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-aceticacid methyl ester (Compound 23, 0.01 g, 0.027 mmol), methanol (1 mL),tetrahydrofuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate(0.042 g, 1 mmol) the title compound was obtained as a pale yellow solidfoam (0.0065 g, 68%). ¹H-NMR (300 MHz, CDCl₃): δ0.35-0.52(m, 4H),1.24(s, 6H), 1.74(m, 1H), 2.59(s, 2H), 3.64(s, 2H), 3.71(s, 2H), 7.03(d, J=8.2 Hz, 1H), 7.22(dd, J=1.4, 7.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H),7.46 (d, J=8.2 Hz, 2H), 7.47(s, 1H).

1-(Iso-propyl-methyl-amino)-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 28)

[0408] Following general procedure G and using a solution of4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene2-one (Intermediate 12, 0.2 g, 0.78 mmol), dichloromethane (4 mL),acetonitrile (2 mL), acetic acid (1 mL), isopropyl amine (1 mL, 11.74mmol) and sodium cyanoborohydride (0.19 g, 3.02 mmol), after 15 days ofreaction time and work up afforded an intermediate (0.14 g, 60%, 0.47mmol) which was used following general procedure H along with acetone (2mL), potassium carbonate (0.6 g, 4.34 mmol) and methyl iodide (0.5 mL, 8mmol). The crude product after work up was subjected to flash columnchromatography over silica gel (230-400 mesh) using 15% ethyl acetate inhexane as the eluent to afford the title compound as a pale yellow oil(0.14 g, 95%).

[0409]¹H-NMR (300 MHz, CDCl₃): δ0.001(s, 9H), 0.85 (d, J=6.4 Hz, 6H),0.98 (s, 3H), 1.03 (s, 3H), 1.32-1.60 (m, 4H), 1.81(s, 3H), 2.64(heptet,J=6.4 Hz, 1H, 3.65 (dd, J=6.1, 9.4 Hz, 1H), 6.97 (dd, J=1.7, 7.9 Hz,1H), 7.13 (d, J=1.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H).

6-Ethynyl-1-(iso-propyl-methyl-amino)-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 29)

[0410] Following general procedure E and using1-(methyl-iso-propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 28, 0.14 g, 0.45 mmol), methanol (5 mL), potassiumcarbonate (0.61 g, 4.41 mmol) and ethyl acetate the title compound(0.092 g, 80%) was obtained as an oil.

[0411]¹H-NMR (300 MHz, CDCl₃): δ1.11 (d, J=6.4 Hz, 6H), 1.23(s, 3H),1.28(s, 3H), 1.51-1.87 (m, 4H), 2.09(s, 3H), 2.90 (heptet, J=6.4 Hz,1H), 3.00(s, 1H), 3.91 (dd, J=5.8, 10.0 Hz, 1H), 7.25(dd, J=1.7, 8.2 Hz,1H), 7.41 (d, J=1.7 Hz, 1H), 7.70(d, J=8.2 Hz, 1H).

4-[5-(Iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)]-benzoicAcid Ethyl Ester (Compound 25, General Formula 4)

[0412] Following general procedure F and6-ethynyl-1-(iso-propyl-methyl-amino)-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene(Intermediate 29, 0.092 g, 0.36 mmol), Ethyl-4-iodo benzoate (Reagent A,0.12 g, 0.48 mmol), triethyl amine (1 mL), tetrahydrofuran (2 mL),copper(I)iodide (0.028 g, 0.14 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10-15% ethyl acetate in hexane as the eluent the title compoundwas obtained (0.04 g, 27%).

[0413]¹H-NMR (300 MHz, CDCl₃): δ1.12 (d, J=6.5 Hz, 6H), 1.27 (s, 3H),1.31 (s, 3H), 1.40 (t, J=7.0 Hz, 3H), 1.62-1.89 (m, 4H), 2.10(s, 3H),2.92 (heptet, J=6.4 Hz, 1H), 3.94(dd, J=6.1, 9.7 Hz, 1H), 4.38(q, J=7.1Hz, 2H), 7.31(dd, J=1.4, 8.2 Hz, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.58 (d,J=8.2 Hz, 2H), 7.75(d, J=8.2 Hz, 1H), 8.01(d, J=8.2 Hz, 2H).

4-[5-(Iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)]-benzoicAcid (Compound 26, General Formula 4)

[0414] Following general procedure I and using4-[5-(iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)]-benzoicAcid Ethyl Ester (Compound 25, 0.04 g, 0.01 mmol), ethanol (2 mL),tetrahydrofuran (1 mL) and 1M aqueous sodium hydroxide solution (1 mL)followed by recrystallization from diethylether-hexane, the titlecompound was obtained as an off-white solid (0.010 g, 27%).

[0415]¹H-NMR (300 MHz, CDCl₃): δ1.30(d, J=6.0 Hz, 6H), 1.31(s, 9H),1.67-1.98(m, 4H), 2.35 (s, 3H), 3.19 (heptet, J=6.4 Hz, 1H), 4.36 (t,J=7.6 Hz, 1H), 7.28(dd, J=1.4, 8.2 Hz, 1H), 7.48 (d, J=1.4 Hz, 1H), 7.55(d, J=8.2 Hz, 2H), 7.81 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.2 Hz, 2H).

[4-(2,2,4,4-Tetramethyl-chroman-6-yl-ethynyl)phenyl]Acetic Acid MethylEster (Compound 27, General Formula 8)

[0416] Following general procedure F and using6-ethynyl-2,2,4,4-tetramethylchroman (synthesis described in U.S. Pat.Nos. 5,045,551 and 5,616,597 incorporated herein by reference) (0.060 g,0.28 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.078 g, 0.28mmol), triethyl amine (4 mL), tetrahydrofuran (4 mL), copper(I)iodide(0.030 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.1 g, 0.16 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent thetitle compound was obtained (0.047 g, 46%).

[0417]¹H NMR (300 MHz, CDCl₃): δ7.48-7.45 (m, 3H), 7.25-7.23 (m, 3H),6.75 (d, 1H, J=8.2 Hz), 3.70 (s, 3H), 3.62 (s, 2H), 1.84 (s, 2H), 1.36(s, 6H), 1.35 (s, 6H).

General Procedure L:[4-(2,2,4,4-Tetramethyl-chroman-6-yl-ethynyl)phenyl] Acetic Acid(Compound 28, General Formula 8)

[0418] A solution of[4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] acetic acid methylester (Compound 27, 0.047 g, 0.13 mmol) in 5 mL of methanol was treatedwith 1M sodium hydroxide solution (2 mL) and heated at 55° C. for 2 h.The volatiles were distilled off in vacuo and the residue was acidifiedwith 10% hydrochloric acid and extracted with ethyl acetate (×2). Thecombined organic phase was washed with brine (×1), dried over anhydroussodium sulfate, filtered and evaporated in vacuo to a residue which waspurified by preparative reverse phase HPLC using 10% water inacetonitrile as the mobile phase to afford the title compound (0.034 g,82%). ¹H NMR (300 MHz, CDCl₃): δ7.49-7.45 (m, 3H), 7.26-7.22 (m, 3H),6.75 (d, 1H, J=8.2 Hz), 3.65 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35(s, 6H).

2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic AcidMethyl Ester (Compound 29, General Formula 8)

[0419] Following general procedure F and using6-ethynyl-2,2,4,4-tetramethylchroman (0.11 g, 0.51 mmol),methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.14 g, 0.51 mmol), triethylamine (5 mL), tetrahydrofuran(10 mL), copper(I)iodide (0.030 g, 0.16mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.16mmol) followed by flash column chromatography over silica gel (230-400mesh) using 5-10% ethyl acetate in hexane as the eluent, the titlecompound was obtained (0.14 g, 79%).

[0420]¹H NMR (300 MHz, CDCl₃): δ7.82 (t, 1H, J=7.9 Hz), 7.39 (d, 1H,J=1.8 Hz), 7.25-7.16 (m, 3H), 6.69 (d, 1H, J=8.2 Hz), 3.85 (s, 3H), 1.77(s, 2H), 1.29 (s, 6H), 1.28 (s, 6H).

2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic Acid(Compound 30, General Formula 8)

[0421] Following general procedure L and using2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acidmethyl ester (Compound 29, 0.14 g, 0.4 mmol), 5 mL of methanol and 1Msodium hydroxide solution (2 mL) followed by recrystallization fromethyl acetate, the title compound was obtained (0.083 g, 58%).

[0422]¹H NMR (300 MHz, CD₃COCD₃): δ8.00 (t, 1H, J=7.8 Hz), 7.63 (d, 1H,J=2.1 Hz), 7.45 (dd, 1H, J=1.5, 7.9 Hz), 7.38 (dd, 1H, J=1.5, 11.4 Hz),7.32 (dd, 1H, J=2.1, 8.2 Hz), 6.81 (d, 1H, J=8.5 Hz), 1.92 (s, 2H), 1.41(s, 6H), 1.38 (s, 6H).

[2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] AceticAcid Ethyl Ester (Compound 31, General Formula 8)

[0423] Following general procedure F and using6-ethynyl-2,2,4,4-tetramethylchroman (0.204 g, 0.95 mmol),ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.263 g, 0.86 mmol),triethyl amine, tetrahydrofuran, copper(I)iodide (0.025 g, 0.13 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.21 g, 62%).

[0424]¹H NMR (300 MHz, CDCl₃): δ7.46 (d, 1H, J=2.1 Hz), 7.25-7.21 (m,4H), 6.69 (d, 1H, J=8.5 Hz), 4.16 (q, 2H, J=7.1 Hz), 3.65 (s, 2H), 1.82(s, 2H), 1.35 (s, 6H), 1.35 (s, 6H), 1.24 (t, 3H, J=7.2 Hz).

[2-Fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl]Acetic Acid(Compound 32, General Formula 8)

[0425] Following general procedure L and using[2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl] acetic acidethyl ester (Compound 31, 0.21 g, 0.58 mmol), 5 mL of methanol and 1Msodium hydroxide solution (2 mL) followed by flash column chromatographyover silica gel (230-400 mesh) using 50% ethyl acetate in hexane, thetitle compound was obtained as a solid (0.184 g, 93%).

[0426]¹H NMR (300 MHz, CDCl₃): δ11.40 (br s, 1H), 7.48 (d, 1H, J=1.8Hz), 7.46-7.16 (m, 4H), 6.76 (d, 1H, J=8.2 Hz), 3.69 (s, 2H), 1.82 (s,2H), 1.34 (s, 12H).

3-Methyl-but-2-enoic Acid 4-bromo-phenyl Ester

[0427] To a stirred, cooled (ice bath) suspension of sodium hydride (2.4g, 100 mmol) in anhydrous tetrahydrofuran (200 mL), 4-bromo phenol (17.3g, 100 mmol) was added followed by 3,3,-dimethyl acryloyl chloride(11.14 mL, 100 mmol). After 4 hours at ambient temperature, the reactionmixture was poured into brine and extracted with diethyl ether (×2). Thecombined organic phase was dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to afford an oil which was subjected to flashcolumn chromatography over silica gel (230-400 mesh) using 2% ethylacetate in hexane as the eluent to afford the title compound (15 g,59%).

[0428]¹H-NMR (300 MHz, CDCl₃): δ2.00(s, 3H), 2.23(s, 3H), 5.89(s, 1H),7.00(d, J=8.8 Hz, 2H), 7.49(d, J=8.8 Hz, 2H).

6-Bromo-4,4-dimethyl-chroman-2-one

[0429] A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7g, 27.6 mmol) in anhydrous dichloromethane (200 mL) was cooled (icebath) and treated with aluminum chloride (6.6 g, 49.6 mmol) and thereaction mixture was stirred overnight at ambient temperature. Thereaction mixture was quenched with saturated aqueous sodium bicarbonatesolution and extracted with diethyl ether (×2). The combined organicextract was washed with brine (×1), dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford an oil which was purified byflash column chromatography over silica gel (230-400 mesh) using 2.5%ethyl acetate in hexane as the eluent to afford the title compound (4.2g, 57%).

[0430]¹H-NMR (300 MHz, CDCl₃): δ1.36(s, 6H), 2.62(s, 2H), 6.95(d, J=8.5Hz, 1H), 7.37(dd, J=2.4, 8.5 Hz, 1H), 7.43(d, J=2.3 Hz, 1H).

4-Bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol

[0431] A solution of 6-bromo-4,4-dimethyl-chroman-2-one (1 g, 3.92 mmol)in anhydrous tetrahydrofuran (20 mL) was treated with 3M solution ofethyl magnesium bromide (2.6 mL) and stirred at ambient temperature for2 hours. The reaction mixture was poured into cold dilute hydrochloricacid and extracted with ethyl acetate (×2). The combined organic extractwas dried over anhydrous sodium sulfate, filtered and evaporated invacuo to afford a residue which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 10% ethyl acetate inhexane as the eluent to afford the title compound as a pale yellow solid(1.1 g, 100%).

[0432]¹H-NMR (300 MHz, CDCl₃): δ1.14(s, 6H), 1.44(s, 6H), 2.20(s, 2H),6.49(d, J=8.4 Hz,1H), 7.15(dd, J=2.4, 8.5 Hz, 1H), 7.37(d, J=2.4 Hz,1H).

6-Bromo-2,2,4,4-tetramethyl-chroman

[0433] A solution of 4-bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol(1.1 g, 3.92 mmol) and p-toluene sulfonic acid (0.744 g, 3.92 mmol) inbenzene (20 mL) was refluxed overnight. The reaction mixture cooled toambient temperature, filtered on silica gel and washed with 10% ethylacetate in hexane. The filtrate and washings were evaporated in vacuo toan oil which was subjected to flash column chromatography over silicagel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent toafford the title compound as a pale yellow oil (0.84 g, 80%).

[0434]¹H-NMR (300 MHz, CDCl₃): δ1.34(s, 6H), 1.35(s, 6H), 1.82(s, 2H),6.68(d, J=8.4 Hz, 1H), 7.16(dd, J=2.7, 8.7 Hz, 1H), 7.37(d, J=2.6 Hz,1H).

[0435] The synthesis of this compound, as described here, is in closeanalogy to the synthesis of 6-bromo-2,2,4,4-tetramethylthiochroman, asdescribed in U.S. Pat. No. 5,045,551.

2,2,4,4-tetramethyl-6-(2-trimethylsilyl)ethynyl Chroman

[0436] Following general procedure D and using6-bromo-2,2,4,4-tetramethyl chroman (0.5 g, 1.87 mmol), triethyl amine(5 mL), anhydrous tetrahydrofuran (15 mL), copper(I)iodide (0.107 g,0.156 mmol), trimethylsilyl acetylene (1.84 g, 18.7 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.39 g, 0.56 mmol) thetitle compound was obtained as a brown oil (0.61 g, 100%).

[0437]¹H NMR (300 MHz, CDCl₃): δ7.43 (d, 1H, J=2.1 Hz), 7.23 (dd, 1H,J=7.9, 2.1 Hz), 6.73 (d, 1H, J=8.2 Hz), 1.83 (s, 2H), 1.36 (s, 12H),0.28 (s, 9H).

6-Ethynyl-2,2,4,4-tetramethyl Chroman

[0438] Following general procedure E and using2,2,4,4-tetramethyl-6-(2-trimethylsilyl)ethynyl chroman (0.61 g, 1.87mmol), potassium carbonate (1.9 g, 13.74 mmol) and methanol the titlecompound was obtained (0.4 g, 90%).

[0439]¹H NMR (300 MHz, CDCl₃): δ7.47 (d, 1H, J=2.1 Hz), 7.24 (dd, 1H,J=7.9, 2.1 Hz), 6.76 (d, 1H, J=8.2Hz), 3.01 (s, 1H), 1.85 (s, 2H), 1.37(s, 6H), 1.36 (s, 6H).

[0440] An alternative synthesis for this compound is described in U.S.Pat. Nos. 5,045,551 and 5,616,597.

General Procedure M: 6-Bromo-2,2,4,4-tetramethyl-chroman-8-carbaldehyde(Intermediate 30)

[0441] A stirred, cooled (ice bath) solution of6-bromo-2,2,4,4-tetramethyl chroman, (0.5 g, 1.865 mmol) in anhydrousdichloromethane (5 mL) was treated with a 1M solution (1.86 mL, 1.86mmol) of titanium tetrachloride in dichloromethane followed byα,α-dichloro methyl ether (0.214 g, 1.865 mmol). The reaction mixturewas allowed to warm to ambient temperature for 4 h. The reaction mixturewas diluted with diethyl ether, washed with brine (×1) and dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to a residuewhich was subjected to flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane to afford the titlecompound as a yellow solid (0.52 g, 94%).

[0442]¹H NMR (300 MHz, CDCl₃): δ10.38 (s, 1H), 7.72 (d, 1H, J=2.6 Hz),7.57 (d, 1H, J=2.6 Hz), 1.88 (s, 2H), 1.41 (s, 6H), 1.36 (s, 6H).

General Procedure N: 6-Bromo-8-vinyl-2,2,4,4-tetramethyl-chroman(Intermediate 31)

[0443] A solution of methylidene triphenyl phosphorane [generated frommethyl triphenylphosphonium bromide (7 g, 20 mmol) and (11.8 mL, 19mmol) of a 1.6M solution of n-butyl lithium in hexanes] was added6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30,0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted withhexane, washed with brine (×1), dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to a clear oil which was subjected toflash column chromatography over silica gel (230-400 mesh) using 2%ethyl acetate in hexane as the eluent to afford the title compound as aclear oil (0.37 g, 72%).

[0444]¹H NMR (300 MHz, CDCl₃): δ7.46 (d, 1H, J=2.5 Hz), 7.33 (d, 1H,J=2.5 Hz), 7.03 (dd, 1H, J=11.3, 17.9 Hz), 5.75 (dd, 1H, J=1.4, 17.9Hz), 5.30 (dd, 1H, J=1.4, 11.3 Hz), 1.85 (s, 2H), 1.39 (s, 6H), 1.37 (s,6H).

General Procedure O: 6-Bromo-8-cyclopropyl-2,2,4,4-tetramethyl Chroman(Intermediate 32)

[0445] A stirred, cooled (−30° C.) solution of6-bromo-8-vinyl-2,2,4,4-tetramethyl chroman (Intermediate 31, 0.37 g,1.26 mmol) in diethyl ether was treated with a solution of diazomethanein diethyl ether and catalytic amount of palladium (II)acetate (˜30 mg).The reaction mixture was allowed to warm to ambient temperature andsubjected to flash column chromatography over silica gel (230-400 mesh)using 2% ethyl acetate in hexane as the eluent to afford the titlecompound as a clear, pale yellow oil (0.376 g, 97%).

[0446]¹H NMR (300 MHz, CDCl₃): δ7.17 (d, 1H, J=2.3 Hz), 6.73 (d, 1H,J=2.6Hz), 2.19-2.16 (m, 1H), 1.83 (s, 2H), 1.37 (s, 6H), 1.33 (s, 6H),0.94-0.88 (m, 2H), 0.64-0.59 (m, 2H).

8-Cyclopropyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl Chroman(Intermediate 33)

[0447] Following general procedure D and using6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32,0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethylamine (3 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.025g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g,0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).

[0448]¹H NMR (300 MHz, CDCl₃): δ7.36 (d, 1H, J=2.2 Hz), 6.90 (d, 1H,J=1.9 Hz), 2.31-2.22 (m, 1H), 1.96 (s, 2H), 1.49 (s, 6H), 1.46 (s, 6H),1.05-0.88 (m, 2H), 0.78-0.72 (m, 2H), 0.37 (s, 9H).

8-Cyclopropyl-6-ethynyl-2,2,4,4-tetramethyl chroman (Intermediate 34)

[0449] Following general procedure E and using8-cyclopropyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman(Intermediate 33, 0.17 g, 0.68 mmol), methanol and potassium carbonate(0.2 g, 1.47 mmol) the title compound was obtained as an oil (0.064 g,47%).

[0450]¹H NMR (300 MHz, CDCl₃): δ7.38 (d, 1H, J=1.9 Hz), 6.92 (d, 1H,J=1.9 Hz), 3.08 (s, 1H), 2.32-2.23 (m, 1H), 1.96 (s, 2H), 1.50 (s, 6H),1.46 (s, 6H), 1.05-0.99 (m, 2H), 0.77-0.72 (m, 2H).

4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic AcidEthyl Ester (Compound 33, General Formula 8)

[0451] Following general procedure F and using8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.1g, 0.38 mmol), ethyl-4-iodo-benzoate (Reagent A, 0.1 g, 0.34 mmol),triethyl amine (5 mL), tetrahydrofuran (10 mL), copper(I)iodide (0.025g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g,0.11 mmol) followed by flash column chromatography over silica gel(230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, thetitle compound was obtained (0.135 g, 89%).

[0452]¹H NMR (300 MHz, CDCl₃): δ8.00 (d, 2H, J=8.2 Hz), 7.55 (d, 2H,J=8.2 Hz), 7.30 (d, 1H, J=1.8 Hz), 6.84 (d, 1H, J=2.0 Hz), 4.38 (q, 2H,J=6.9 Hz), 2.22-2.12 (m, 1H), 1.85 (s, 2H), 1.40 (t, 3H, J=6.9 Hz), 1.38(s, 6H), 1.36 (s, 6H), 0.92-0.88 (m, 2H), 0.67-0.62 (m, 2H).

4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid(Compound 34, General Formula 8)

[0453] Following general procedure L and using4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acidethyl ester (Compound 33, 0.135 g, 0.34 mmol), 5 mL of methanol and 1Msodium hydroxide solution (2 mL) followed by preparative reverse phaseHPLC using 10% water in acetonitrile as the mobile phase, the titlecompound was obtained as a solid (0.093 g, 73%).

[0454]¹H NMR (300 MHz, CDCl₃): δ11.26 (br s, 1H), 8.08 (d, 2H, J=8.2Hz), 7.59 (d, 2H, J=8.2 Hz), 7.31 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=2.1Hz), 2.22-2.13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H),0.95-0.87 (m, 2H), 0.68-0.63 (m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl]acetic Acid Methyl Ester (Compound 35, General Formula 8)

[0455] Following general procedure F and using8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34,0.096 g, 0.38 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.094 g,0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL),copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) thetitle compound was obtained (0.137 g, 90%). ¹H NMR (300 MHz, CDCl₃):δ7.47 (d, 2H, J=7.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.24 (d, 2H, J=7.9 Hz),6.82 (d, 1H, J=2.1 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.13 (m, 1H),1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63(m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl]acetic acid (Compound 36, General Formula 8)

[0456] Following general procedure L and using[4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl) phenyl]acetic acid methyl ester (Compound 35, 0.137 g, 0.30 mmol), 5 mL ofmethanol and 1M sodium hydroxide solution (2 mL) followed by preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phase,the title compound was obtained as a solid (0.11 g, 80%).

[0457]¹H NMR (300 MHz, CDCl₃): δ11.56 (br s, 1H), 7.47 (d, 2H, J=8.9Hz), 7.28 (d, 1H, J=1.9 Hz), 7.23 (d, 2H, J=8.5 Hz), 6.82 (d, 1H, J=1.9Hz), 3.62 (s, 2H), 2.21-2.12 (m, 1H), 1.83 (s, 2H), 1.36 (s, 6H), 1.34(s, 6H), 0.93-0.82 (m, 2H), 0.72-0.62 (m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]Acetic Acid Ethyl Ester (Compound 37, General Formula 8)

[0458] Following general procedure F and using8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34,0.096 g, 0.38 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C,0.104 g, 0.34 mmol), triethyl amine (3 mL), tetrahydrofuran (3 mL),copper(I)iodide (0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) thetitle compound was obtained (0.14 g, 85%).

[0459]¹H NMR (300 MHz, CDCl₃): δ7.31 (d, 1H, J=1.9 Hz), 7.29-7.21 (m,3H), 6.85 (d, 1H, J=1.9 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.68 (s, 2H),2.24-2.14 (m, 1H), 1.87 (s, 2H), 1.40 (s, 6H), 1.38 (s, 6H), 1.28 (t,3H, J=7.1 Hz), 0.96-0.85 (m, 2H), 0.70-0.64 (m, 2H).

[4-(8-Cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]Acetic Acid (Compound 38, General Formula 8)

[0460] Following general procedure L and using[4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid ethyl ester (Compound 37, 0.14 g, 0.323 mmol), 5 mL ofmethanol and 1M sodium hydroxide solution (2 mL) followed by reversephase HPLC using 10% water in acetonitrile as the mobile phase, thetitle compound was obtained as a solid (0.110 g, 80%).

[0461]¹H NMR (300 MHz, CDCl₃): δ7.28 (d, 1H, J=2.1 Hz), 7.27-7.17 (m,3H), 6.82 (d, 1H, J=1.8 Hz), 3.70 (s, 2H), 2.21-2.11 (m, 1H), 1.84 (s,2H), 1.37 (s, 6H), 1.35 (s, 6H), 0.94-0.87 (m, 2H), 0.67-0.62 (m, 2H).

General Procedure P: 6-Bromo-4,4-dimethyl-2-methylene Chroman(Intermediate 35)

[0462] A stirred, cooled (ice bath) solution of6-bromo-4,4-dimethyl-chroman-2-one available in accordance with U.S.Pat. No. 5,399,561 incorporated herein by reference (1 g, 3.92 mmol) in8 mL of anhydrous tetrahydrofuran was treated with a 0.5 M solution ofμ-chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminum(Tebbe reagent) in toluene (8.23 mL, 4.12 mmol). After 10 minutes, thereaction mixture was poured into ice-water mixture containing 50 mL of1M sodium hydroxide and extracted with hexane. The hexane extract waswashed with brine (×1), filtered over a bed of celite and evaporated invacuo to an oil which was subjected to flash column chromatography oversilica gel (230-400 mesh) using hexane as the eluent to afford the titlecompound (0.74 g, 74%) as a clear oil.

[0463]¹H NMR (300 MHz, CDCl₃): δ7.34 (d, 1H, J=2.3 Hz), 7.23 (dd, 1H,J=2.3, 8.5 Hz), 6.77 (d, 1H, J=8.0 Hz), 4.61 (d, 1H, J=0.73 Hz), 4.17(d, 1H, J=0.73 Hz), 2.33 (s, 2H), 1.27 (s, 6H).

General Procedure Q:6-Bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 36)

[0464] A solution of diethyl zinc in hexane (1M, 7.1 mL) was treatedwith diiodomethane (1.89 g, 7.1 mmol). After 5 minutes, a solution of6-bromo-4,4-dimethyl-2-methylene chroman (Intermediate 35, 0.44 g, 1.77mmol) in 3 mL of hexane was added and the solution was refluxed for 1 h.The reaction mixture was then cooled to ambient temperature, dilutedwith hexane, washed with brine (×1), dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to a residue which wassubjected to flash column chromatography over silica gel (230-400 mesh)using hexane as the eluent to obtain the title compound (0.44 g, 93%).

[0465]¹H NMR (300 MHz, CDCl₃): δ7.47 (d, 1H, J=2.3 Hz), 7.23 (dd, 1H,J=2.3, 8.5 Hz), 6.70 (d, 1H, J=8.0 Hz), 1.96 (s, 2H), 1.47 (s, 6H),1.09-1.05 (m, 2H), 0.74-0.70 (m, 2H).

3,4-Dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 37)

[0466] Following general procedure D and using6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 36, 0.44 g, 1.65 mmol), triethyl amine (4 mL), anhydroustetrahydrofuran (5 mL), copper(I)iodide (0.95 g, 0.5 mmol),trimethylsilyl acetylene (1.62 g, 16.5 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.56 mmol), thetitle compound was obtained as a brown oil (0.4 g, 86%).

[0467]¹H NMR (300 MHz, CDCl₃): δ7.44 (d, 1H, J=2.1 Hz), 7.18 (dd, 1H,J=2.1, 8.5 Hz), 6.65 (d, 1H, J=8.5 Hz), 1.87 (s, 2H), 1.37 (s, 6H),1.01-0.97 (m, 2H), 0.65-0.61 (m, 2H), 0.26 (s, 9H).

6-Ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38)

[0468] Following general procedure E and using3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 37, 0.4 g, 1.42 mmol), potassium carbonate (0.98 g, 7.1mmol) and methanol, the title compound was obtained as a yellow oil (0.3g, 100%).

[0469]¹H NMR (300 MHz, CDCl₃): δ7.44 (d, 1H, J=2.1 Hz), 7.18 (dd, 1H,J=2.1, 8.5 Hz), 6.65 (d, 1H, J=8.5 Hz), 2.97 (s, 1H), 1.86 (s, 2H), 1.37(s, 6H), 1.00-0.95 (m, 2H), 0.64-0.59 (m, 2H).

Benzoic Acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylEster (Compound 39, General Formula 1)

[0470] Following general procedure F and using6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38, 0.06 g, 0.28 mmol), ethyl-4-iodo-benzoate (Reagent A,0.086 g, 0.31 mmol), triethyl amine (4 mL), tetrahydrofuran (4 mL),copper(I)iodide (0.032 g, 0.17 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.118 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.07 g, 70%).

[0471]¹H NMR (300 MHz, CDCl₃): δ8.01 (d, 2H, J=8.2 Hz), 7.56 (d, 2H,J=8.5 Hz), 7.49 (d, 1H, J=2.1 Hz), 7.24 (dd, 1H, J=2.1,8.5 Hz), 6.70 (d,1H, J=8.5 Hz), 4.38 (q, 2H, J=7.1 Hz), 1.89 (s, 2H), 1.40 (s, 6H), 1.40(t, 3H, J=7.0 Hz), 1.02-0.98 (m, 2H), 0.67-0.62 (m, 2H).

Benzoic acid,4-[(3.4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 40, General Formula 1)

[0472] Following general procedure L and using benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethyl ester (Compound 39, 0.07 g, 0.196mmol), 5 mL of ethanol and 1M sodium hydroxide solution (2 mL) followedby preparative reverse phase HPLC using 10% water in acetonitrile as themobile phase, the title compound was obtained as a solid (0.034 g, 52%).

[0473]¹H NMR (300 MHz, CD₃COCD₃): δ8.05 (d, 2H, J=8.2 Hz), 7.64 (d, 2H,J=8.2 Hz), 7.60 (d, 1H, J=2.1 Hz), 7.28 (dd, 1H, J=2.1, 8.5 Hz), 6.73(d, 1H, J=8.5 Hz), 1.95 (s, 2H), 1.43 (s, 6H), 0.96-0.92 (m, 2H),0.74-0.71 (m, 2H).

Benzeneacetic Acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylEster (Compound 41, General Formula 1)

[0474] Following general procedure F and using6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38,0.060 g, 0.28 mmol), methyl-4-iodo phenyl acetate(Reagent B, 0.078 g, 0.28 mmol), triethyl amine (4 mL), tetrahydrofuran(4 mL), copper(I)iodide (0.032 g, 0.17 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.118 g, 0.17 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5% ethyl acetate in hexane as the eluent, the title compound wasobtained (0.084 g, 84%).

[0475]¹H NMR (300 MHz, CDCl₃): δ7.48-7.45 (m, 3H), 7.26-7.20 (m, 3H),6.67 (d, 1H, J=8.5 Hz), 3.70 (s, 3H), 3.63 (s, 2H), 1.89 (s, 2H), 1.40(s, 3H), 1.40 (s, 3H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).

Benzeneacetic Acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 42, Formula 1)

[0476] A solution of benzeneacetic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 41, 0.084 g, 0.24 mmol) in 5 mL of methanol was treatedwith 1M sodium hydroxide solution (2 mL) and heated at 55° C. for 2 h.The volatiles were distilled off in vacuo and the residue was acidifiedwith 10% hydrochloric acid and extracted with ethyl acetate (×2). Thecombined organic phase was washed with brine (×1), dried over anhydroussodium sulfate, filtered and evaporated in vacuo to a residue which waspurified by preparative reverse phase HPLC using 10% water inacetonitrile as the mobile phase to afford the title compound (0.080 g,100%).

[0477]¹H NMR (300 MHz, CD₃COCD₃): δ7.49-7.46 (m, 3H), 7.25 (d, 2H, J=8.2Hz), 7.22 (dd, 1H J=2.1, 8.5 Hz), 6.68 (d, 1H, J=8.5 Hz), 3.66 (s, 2H),1.88 (s, 2H), 1.44 (s, 6H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).

2-Fluoro-benzoic Acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylEster (Compound 43, General Formula 1)

[0478] Following general procedure F and6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 38, 0.050 g, 0.23 mmol), methyl-2-fluoro-4-iodo-benzoate(Reagent G, 0.069 g, 0.24 mmol), triethyl amine (5 mL), tetrahydrofuran(5 mL), copper(I)iodide (0.013 g, 0.07 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.049 g, 0.07 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.080 g, 100%).

[0479]¹H NMR (300 MHz, CDCl₃): δ7.90 (t, 1 H, J=7.9 Hz), 7.63 (d, 1H,J=1.8 Hz), 7.32 (dd, 1H, J=1.5, 8.2 Hz), 7.26 (dd, 1H, J=1.5, 11.4 Hz),7.24 (dd, 1H, J=2.1, 8.5 Hz), 6.71 (d, 1H, J=8.5 Hz), 1.97 (s, 2H), 1.44(s, 6H), 0.98-0.94 (m, 2H), 0.76-0.71 (m, 2H).

2-Fluoro-benzoic Acid4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 44, General Formula 1)

[0480] Following general procedure L and using 2-fluoro-benzoic acid,4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 43, 0.08 g, 0.23 mmol), 5 mL of methanol and 2M sodiumhydroxide solution (1 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using ethyl acetate as the eluent, the titlecompound was obtained (0.020 g, 25%).

[0481]¹H NMR (300 MHz, CD₃COCD₃): δ7.99 (t, 1H, J=7.9 Hz), 7.63 (d, 1H,J=2.1 Hz), 7.44 (dd, 1H, J=1.5, 7.9 Hz), 7.37 (dd, 1H, J=1.5, 11.4 Hz),7.31 (dd, 1H, J=2.1, 8.5 Hz), 6.75 (d, 1H, J=8.2 Hz), 1.97 (s, 2H), 1.44(s, 6H), 0.98-0.94 (m, 2H), 0.76-0.71 (m, 2H).

General Procedure R: 2,2,4,4-Tetramethyl-chroman-6-carboxylic Acid(Intermediate 39)

[0482] A stirred, cooled (−78° C.) solution of6-bromo-2,2,4,4-tetramethyl chroman (1.2 g, 4.47 mmol) in 15 mL ofanhydrous tetrahydrofuran was treated with a 1.7M solution of tert-butyllithium solution in pentane (5.27 mL, 8.9 mmol). After 10 minutes at−78° C., carbon dioxide (generated from dry ice) was bubbled into thereaction mixture. The reaction mixture was allowed to warm to ambienttemperature. The reaction mixture was diluted with ethyl acetate, washedwith brine, dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo to a residue which was subjected to flash column chromatographyover silica gel (230-400 mesh) using ethyl acetate as the eluent toafford the title compound as a white solid (1.1 g, 92%).

[0483]¹H NMR (300 MHz, CDCl₃): δ12.17 (br s, 1H), 8.09 (d, 1H, J=2.1Hz), 7.85 (dd, 1H, J=2.1, 8.5 Hz), 6.83 (d, 1H, J=8.2 Hz), 1.87 (s, 2H),1.39 (s, 6H), 1.37 (s, 6H).

2,2,4,4-Tetramethyl-chroman-6-carboxylic Acid4-(tert-butoxycarbonylmethyl)phenyl Ester (Compound 45, General Formula8)

[0484] A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1g, 0.43 mmol) in thionyl chloride (10 mL) was refluxed for 2 h. Thethionyl chloride was evaporated under reduced pressure and the residuewas dissolved in 5 mL of dichloromethane and treated with triethyl amine(5 mL) followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088g, 0.427 mmol). After 0.5 h, the reaction mixture was subjected to flashcolumn chromatography over silica gel (230-400 mesh) using 5-10% ethylacetate in hexane as the eluent to afford the title compound (0.1 g,55%).

[0485]¹H NMR (300 MHz, CDCl₃): δ8.15 (d, 1H, J=2.1 Hz), 7.93 (dd, 1H,J=2.1, 8.5 Hz), 7.33 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz), 6.88 (d,1H, J=8.5 Hz), 3.54 (s, 2H), 1.89 (s, 2H), 1.45 (s, 9H), 1.41 (s, 6H),1.40 (s, 6H).

2,2,4,4-Tetramethyl-chroman-6-carboxylic Acid 4-(carboxymethyl)phenylEster (Compound 46, General Formula 8)

[0486] A solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 45, 0.1 g, 0.23mmol) was treated with 5 mL of trifluoroacetic acid and stirred atambient temperature for 1 h. The trifluoroacetic acid was distilled offunder reduced pressure and the residue was subjected to preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseto afford the title compound as a white solid (0.045 g, 50%).

[0487]¹H NMR (300 MHz, CDCl₃): δ8.13 (d, 1H, J=2.1 Hz), 7.92 (dd, 1H,J=2.3, 8.5 Hz), 7.35 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.5 Hz), 6.87 (d,1H, J=8.5 Hz), 3.68 (s, 2H), 1.89 (s, 2H), 1.41 (s, 6H), 1.39 (s, 6H).

6-Bromo-8-carbaldehyde-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 40)

[0488] Following general procedure M and using6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate36, 2.3 g, 8.65 mmol), anhydrous dichloromethane (25 mL), 1M solution(8.65 mL, 8.65 mmol) of titanium tetrachloride in dichloromethane and(α,α-dichloro methyl ether (1.09 g, 9.52 mmol) followed by flash columnchromatography using 10% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a yellow solid (2.06 g, 81%).

[0489]¹H NMR (300 MHz, CDCl₃): δ10.20 (s, 1H), 7.69 (d, 1H, J=2.6 Hz),7.58 (d, 1H, J=2.6 Hz), 1.92 (s, 2H), 1.40 (s, 6H), 1.09-1.04 (m, 2H),0.73-0.69 (m, 2H).

6-Bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 41)

[0490] Following general procedure N and using A solution of methylidenetriphenyl phosphorane [generated from methyl triphenylphosphoniumbromide (7 g, 20 mmol) and 1.6M solution of n-butyl lithium in hexanes(11.8 mL, 19 mmol)],6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate40, 2.06 g, 7 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as a clear oil (1.36 g, 66%).

[0491]¹H NMR (300 MHz, CDCl₃): δ7.36 (d, 1H, J=2.3 Hz), 7.28 (d, 1H,J=2.6 Hz), 6.80 (dd, 1H, J=11.1, 17.9 Hz), 5.63 (dd, 1H, J=1.2, 17.9Hz), 5.19 (dd, 1H, J=1.2, 11.1 Hz), 1.84 (s, 2H), 1.35 (s, 6H), 0.97 (t,2H, J=6.3 Hz), 0.62 (d, 1H, J=5.3 Hz), 0.60 (d, 1H, J=6.2 Hz).

6-Bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 42)

[0492] Following general procedure O and using A6-bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 41, 1.36 g, 4.6 mmol), a solution of diazomethane indiethyl ether and palladium (II)acetate (˜30 mg) followed by flashcolumn chromatography over silica gel (230-400 mesh) using hexane as theeluent, the title compound was obtained as a clear oil (1.38 g, 100%).

[0493]¹H NMR (300 MHz, CDCl₃): δ7.19 (d, 1H, J=2.2 Hz), 6.71 (d, 1H,J=2.2 Hz), 1.99-1.92 (m, 1H), 1.87 (s, 2H), 1.35 (s, 6H), 1.00-0.95 (m,2H), 0.90-0.82 (m, 2H), 0.65-0.54 (m, 4H).

8-Cyclopropyl-3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 43)

[0494] Following general procedure D and6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 42, 0.74 g, 2.4 mmol),(trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (8 mL),anhydrous tetrahydrofuran, copper(I)iodide (0.050 g, 0.26 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.22 mmol),followed by flash column chromatography over silica gel (230-400 mesh)using 1-2% ethyl acetate in hexane as the eluent, the title compound wasobtained as an oil (0.62 g, 80%).

[0495]¹H NMR (300 MHz, CDCl₃): δ7.28 (d, 1H, J=1.9 Hz), 6.77 (d, 1H,J=1.9 Hz), 2.03-1.94 (m, 1H), 1.91 (s, 2H), 1.40 (s, 6H), 1.05-0.98 (m,2H), 0.95-0.83 (m, 2H), 0.69-0.59 (m, 4H), 0.27 (s, 9H).

8-Cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44)

[0496] Following general procedure E, and8-cyclopropyl-3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 43, 0.62 g, 1.9 mmol), methanol and potassium carbonate(0.5 g, 3.6 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.5 g, 100%).

[0497]¹H NMR (300 MHz, CDCl₃): δ7.30 (d, 1H, J=1.8 Hz), 6.80 (d, 1H,J=2.0 Hz), 2.97 (s, 1H), 2.04-1.95 (m, 1H), 1.91 (s, 2H), 1.39 (s, 6H),1.20-0.90 (m, 2H), 0.90-0.84 (m, 2H), 0.75-0.58 (m, 4H).

Benzeneacetic Acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylEster (Compound 47, General Formula 1)

[0498] Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 44, 0.11 g, 0.43 mmol), methyl-4-iodophenyl acetate (Reagent B, 0.114 g, 0.41 mmol), triethyl amine (5 mL),tetrahydrofuran (3 mL), copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), thetitle compound was obtained as a clear oil (0.096 g, 56%).

[0499]¹H NMR (300 MHz, CDCl₃): δ7.46 (d, 2H, J=8.0 Hz), 7.31 (d, 1H,J=1.9 Hz), 7.24 (d, 2H, J=8.2 Hz), 6.81 (d, 1H, J=1.9 Hz), 3.69 (s, 3H),3.62 (s, 2H), 2.04-1.95 (m, 1H), 1.90 (s, 2H), 1.39 (s, 6H), 1.03-0.99(m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).

Benzeneacetic Acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 48, General Formula 1)

[0500] Following general procedure L and using benzeneacetic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-methylester (Compound 47, 0.96 g, 0.24 mmol), 5 mL of methanol and 1M sodiumhydroxide solution (2 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using 15% methanol in dichloromethane as theeluent, the title compound was obtained as a solid (0.084 g, 91%).

[0501]¹H NMR (300 MHz, CDCl₃): δ10.27 (br s, 1H), 7.46 (d, 2H, J=8.2Hz), 7.30 (d, 1H, J=1.8 Hz), 7.23 (d, 2H, J=8.2 Hz), 6.80 (d, 1H, J=1.5Hz), 3.63 (s, 2H), 2.07-1.94 (m, 1H), 1.89 (s, 2H), 1.39 (s, 6H),1.03-0.98 (m, 2H), 0.89-0.82 (m, 2H), 0.73-0.59 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneaceticAcid Methyl Ester (Compound 49, General Formula 1)

[0502] Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.125 g, 0.5 mmol), methyl-2-fluoro-4-iodo phenylacetate (Reagent H, 0.14 g, 0.5 mmol), triethyl amine (3 mL),tetrahydrofuran (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol)followed by preparative normal phase HPLC using 10% ethyl acetate inhexane as the mobile phase, the title compound was obtained (0.096 g,46%).

[0503]¹H NMR (300 MHz, CDCl₃): δ7.30 (d, 1H, J=2.1 Hz), 7.26-7.18 (m,3H), 6.80 (d, 1H, J=1.8 Hz), 3.71 (s, 3H), 3.67 (s, 2H), 2.04-1.94 (m,1H), 1.90 (s, 2H), 1.40 (s, 6H), 1.18-0.99 (m, 2H), 0.90-0.83 (m, 2H),0.68-0.59 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneaceticAcid (Compound 50, General Formula 1)

[0504] Following general procedure L and using4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneaceticacid methyl ester (Compound 49, 0.096 g, 0.23 mmol), 5 mL of methanoland 1M sodium hydroxide solution (2 mL) followed by flash columnchromatography over silica gel (230-400 mesh) using 15% methanol indichloromethane as the eluent, the title compound was obtained as asolid (0.093 g, 100%).

[0505]¹H NMR (300 MHz, CDCl₃): δ9.50 (br s, 1H), 7.27 (d, 1H, J=2.1 Hz),7.24-7.15 (m, 3H), 6.77 (d, 1H, J=1.5 Hz), 3.67 (s, 2H), 2.01-1.91 (m,1H), 1.87 (s, 2H), 1.36 (s, 6H), 1.01-0.96 (m, 2H), 0.87-0.80 (m, 2H),0.65-0.56 (m, 4H).

Benzoic Acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 51, General Formula 1)

[0506] Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.05 g, 0.2 mmol), ethyl-4-iodo-benzoate (Reagent A,0.055 g, 0.2 mmol), triethyl amine (3 mL), tetrahydrofuran(3 mL),copper(I)iodide(0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), the titlecompound was obtained (0.06 g, 75%).

[0507]¹H NMR (300 MHz, CDCl₃): δ8.00 (d, 2H, J=8.2 Hz), 7.55 (d, 2H,J=8.2 Hz), 7.33 (d, 1H, J=1.8 Hz), 6.83 (d, 1H, J=2.1 Hz), 4.38 (q, 2H,J=7.1 Hz), 2.04-1.95 (m, 1H), 1.91 (s, 2H), 1.40 (s, 6H), 1.40 (t, 3H,J=7.0 Hz), 1.05-0.95 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.61 (m, 4H).

Benzoic Acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 52, General Formula 1)

[0508] Following general procedure L and using benzoic acid,4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-ethylester (Compound 51, 0.06 g, 0.15 mmol), 5 mL of methanol and 1M sodiumhydroxide solution (2 mL) followed by preparative reverse phase HPLCusing 10% water in acetonitrile as the mobile phase, the title compoundwas obtained as a solid (0.040 g, 72%).

[0509]¹H NMR (300 MHz, CDCl₃): δ8.08 (d, 2H, J=8.8 Hz), 7.60 (d, 2H,J=8.8 Hz), 7.34 (d, 1H, J=1.9 Hz), 6.84 (d, 1H, J=1.9 Hz), 2.05-1.96 (m,1H), 1.92 (s, 2H), 1.41 (s, 6H), 1.05-0.95 (m, 2H), 0.92-0.83 (m, 2H),0.75-0.60 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoicAcid Methyl Ester (Compound 53, General Formula 1)

[0510] Following general procedure F and using8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 44, 0.03 g, 0.11 mmol), methyl-2-fluoro-4-iodo-benzoate(Reagent G, 0.025 g, 0.09 mmol), triethyl amine (3 mL),tetrahydrofuran(3 mL), copper(I)iodide (0.020 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol)followed by preparative normal phase HPLC using 10% ethyl acetate inhexane as the mobile phase, the title compound was obtained as a whitesolid (0.019 g, 40%).

[0511]¹H NMR (300 MHz, CDCl₃): δ7.97 (t, 1H, J=7.8 Hz), 7.34 (d, 1H,J=1.9 Hz), 7.32-7.25 (m, 2H), 6.83 (d, 1H, J=1.9 Hz), 3.95 (s, 3H),2.06-1.96 (m, 1H), 1.93 (s, 2H), 1.42 (s, 6H), 1.06-1.02 (m, 2H),0.91-0.86 (m, 2H), 0.71-0.61 (m, 4H).

4-[(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoicAcid (Compound 54, General Formula 1)

[0512] Following general procedure L and using4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoic acid methyl ester(Compound 53, 0.019 g, 0.047 mmol), 5 mL of methanol and 1M sodiumhydroxide solution (2 mL) followed by preparative reverse phase HPLCusing 10% water in acetonitrile as the mobile phase, the title compoundwas obtained as a solid (0.1 g, 56%).

[0513]¹H NMR (300 MHz, CDCl₃): δ7.99 (t, 1H, J=8.0 Hz), 7.36-7.28 (m,3H), 6.83 (d, 1H, J=1.9 Hz), 2.18-1.95 (m, 1H), 1.92 (s, 2H), 1.41 (s,6H), 1.06-1.01 (m, 2H), 0.96-0.83 (m, 2H), 0.76-0.60 (m, 4H).

8-Acetyl-6-bromo-2,2,4,4-tetramethyl Chroman (Intermediate 45)

[0514] A stirred, cooled (ice bath) suspension of aluminum chloride(0.99 g, 7.46 mmol) in anhydrous dichloromethane (20 mL) was treatedwith acetyl chloride (0.58 g, 7.46 mmol). After 5 minutes, a solution of6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.73 mmol) in dichloromethanewas added. The reaction was allowed to warm to ambient temperature andstirred for 2 h. The reaction mixture was then poured into icecontaining 10% hydrochloric acid and extracted with diethyl ether (×2).The combined organic phase was washed with saturated aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to a residue which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 5% ethyl acetate inhexane as the eluent to afford the title compound as a pale yellow oil(0.95 g, 83%). It was used as such for the next step without anycharacterization.

6-Bromo-8-ethyl-2,2,4,4-tetramethyl Chroman (Intermediate 46)

[0515] A stirred, cooled (ice bath) solution of8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 45, 0.95 g,3.1 mmol) in trifluoroacetic acid (10 mL) was treated withtriethylsilane (10 mL) and the resulting reaction mixture was allowed towarm to ambient temperature and stirred overnight. The volatiles weredistilled off in vacuo and the residue was diluted with water andextracted with hexane (×2). The combined organic phase was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to an oilwhich was subjected to flash column chromatography over silica gel(230-400 mesh) using hexane as the eluent to afford the title compoundas a clear oil, contaminated with a small amount to triethylsilane (0.51g, 56%).

[0516]¹H NMR (300 MHz, CDCl₃): δ7.23 (d, 1H, J=2.3 Hz), 7.08 (d, 1H,J=2.3 Hz), 2.58 (q, 2H, J=7.6 Hz), 1.81 (s, 2H), 1.34 (s, 6H), 1.33 (s,6H), 1.17 (t, 3H, J=7.6 Hz).

8-Ethyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl Chroman(Intermediate 47)

[0517] Following general procedure D and using6-bromo-8-ethyl-2,2,4,4-tetramethyl chroman (Intermediate 46, 0.5 g,1.61 mmol), (trimethylsilyl)acetylene (1.57 g, 16.1 mmol), triethylamine (8 mL), anhydrous tetrahydrofuran (10 mL), copper(I)iodide (0.025g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g,0.11 mmol), followed by flash column chromatography over silica gel(230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the titlecompound was obtained as an oil (0.137 g, 27%).

[0518]¹H NMR (300 MHz, CDCl₃): δ7.27 (d, 1H, J=2.1 Hz), 7.10 (d, 1H,J=2.1 Hz), 2.55 (q, 2H, J=7.6 Hz), 1.81 (s, 2H), 1.33 (s, 6H), 1.32 (s,6H), 1.15 (t, 3H, J=7.6 Hz), 0.24 (s, 9H).

8-Ethyl-6-ethynyl-2,2,4,4-tetramethyl Chroman (Intermediate 48)

[0519] Following general procedure E and using8-ethyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman(Intermediate 47, 0.137 g, 0.44 mmol), methanol and potassium carbonate(0.1 g, 0.72 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.066 g, 62%).

[0520]¹H NMR (300 MHz, CDCl₃): δ7.33 (d, 1H, J=2.2 Hz), 7.15 (d, 1H,J=1.6 Hz), 2.99 (s, 1H), 2.59 (q, 2H, J=7.6 Hz), 1.84 (s, 2H), 1.37 (s,6H), 1.35 (s, 6H), 1.19 (t, 3H, J=7.6 Hz).

[4-(8-Ethyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] Acetic AcidMethyl Ester (Compound 55, General Formula 8)

[0521] Following general procedure F and using8-ethyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 48, 0.033 g,0.136 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.034 g, 0.12mmol), triethyl amine (2 mL), tetrahydrofuran (2 mL), copper(I)iodide(0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II)(0.075 g, 0.11 mmol) the title compound was obtained (0.035 g, 73%).

[0522]¹H NMR (300 MHz, CDCl₃): δ7.49 (d, 2H, J=7.9 Hz), 7.35 (d, 1H,J=1.8 Hz), 7.26 (d, 2H, J=7.9 Hz), 7.18 (d, 1H, J=1.9 Hz), 3.72 (s, 3H),3.65 (s, 2H), 2.61 (q, 2H, J b =7.5 Hz), 1.85 (s, 2H), 1.38 (s, 12H),1.21 (t, 3H, J=7.5 Hz).

[4-(8-Ethyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)phenyl] Acetic Acid(Compound 56, General Formula 8)

[0523] Following general procedure L and using[4-(8-ethyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl] acetic acidmethyl ester (Compound 55, 0.035 g, 0.1 mmol), 5 mL of methanol and 1Msodium hydroxide solution (1 mL) followed by preparative reverse phaseHPLC using 10% water in acetonitrile as the mobile phase, the titlecompound was obtained as a solid (0.11 g, 25%).

[0524]¹H NMR (300 MHz, CDCl₃): δ7.48 (d, 2H, J=8.0 Hz), 7.33 (d, 1H,J=1.9 Hz), 7.25 (d, 2H, J=8.0 Hz), 7.15 (d, 1H, J=1.9 Hz), 3.65 (s, 2H),2.59 (q, 2H, J=7.5 Hz), 1.83 (s, 2H), 1.35 (s, 12H), 1.18 (t, 3H, J=7.4Hz).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic Acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49)

[0525] Following general procedure R and using6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 42, 0.45 g, 1.48 mmol), anhydrous tetrahydrofuran (5 mL),1.7M solution of tert-butyl lithium solution in pentane ( 1.74 mL, 2.96mmol) and carbon dioxide generated from dry ice, followed by flashcolumn chromatography over silica gel (230-400 mesh) using 50% ethylacetate in hexane as the eluent, the title compound was obtained as awhite solid (0.34 g, 85%).

[0526]¹H NMR (300 MHz, CDCl₃): δ12.43 (br s, 1H), 7.94 (d, 1H, J=2.1Hz), 7.42 (d, 1H, J=1.8 Hz), 2.06-1.96 (m, 1H), 1.92 (s, 2H), 1.42 (s,6H), 1.12-0.97 (m, 2H), 0.95-0.81 (m, 2H), 0.77-0.60 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,4-(tert-butoxycarbonylmethyl)phenyl Ester (Compound 57, General Formula1)

[0527] A solution ofspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 0.06 g, 0.22mmol) in anhydrous dichloromethane (5 mL) was treated withtert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.05 g, 0.22 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.11 g, 0.22 mmol) and 4-dimethylaminopyridine (0.028 g, 0.22 mmol).The resulting solution was stirred at ambient temperature overnight. Thereaction mixture was subjected to flash column chromatography oversilica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluentto afford the title compound as a clear oil that solidified on standing(0.048 g, 48%).

[0528]¹H NMR (300 MHz, CDCl₃): δ7.91 (d, 1H, J=2.1 Hz), 7.41 (d, 1H,J=1.8 Hz), 7.24 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.5 Hz), 3.46 (s, 2H),1.97-1.90 (m, 1H), 1.87 (s, 2H), 1.37 (s, 9H), 1.36 (s, 6H), 1.04-0.90(m, 2H), 0.87-0.75 (m, 2H), 0.65-0.56 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 4-(carboxymethyl)phenyl ester(Compound 58, General Formula 1)

[0529] A solution ofspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 57, 0.048 g, 0.105mmol) was treated with 2 mL of trifluoroacetic acid and stirred atambient temperature for 2 h. The trifluoroacetic acid was distilled offunder reduced pressure and the residue was subjected to preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseto afford the title compound as a white solid (0.029 g, 55%).

[0530]¹H NMR (300 MHz, CDCl₃): δ7.99 (d, 1H, J=2.2 Hz), 7.48 (d, 1H,J=1.9 Hz), 7.34 (d, 2H, J=8.5 Hz), 7.16 (d, 2H, J=8.5 Hz), 3.67 (s, 2H),2.07-1.97 (m, 1H), 1.95 (s, 2H), 1.44 (s, 6H), 1.09-1.04 (m, 2H),0.93-0.85 (m, 2H), 0.79-0.64 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic Acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-3-(tert-butoxycarbonylmethyl)phenylEster (Compound 59, General Formula 1)

[0531] A solution ofspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 0.05 g, 0.18mmol) in anhydrous dichloromethane (5 mL) was treated withtert-butyl-3-hydroxy phenyl acetate (Reagent F, 0.04 g, 0.18 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.029 g, 0.1 mmol) and 4-dimethylaminopyridine (0.022 g, 0.18 mmol).The resulting solution was stirred at ambient temperature overnight. Thereaction mixture was subjected to flash column chromatography oversilica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluentto afford the title compound as a clear oil that solidified on standing(0.020 g, 23%).

[0532]¹H NMR (300 MHz, CDCl₃): δ7.98 (d, 1H, J=1.9 Hz), 7.48 (d, 1H,J=2.2 Hz), 7.38 (t, 1H, J=7.7Hz), 7.19-7.11 (m, 3H), 3.68 (s, 2H),2.05-1.94 (m, 1H), 1.95 (s, 2H), 1.44 (s, 15H), 1.09-1.04 (m, 2H),0.96-0.82 (m, 2H), 0.73-0.64 (m, 4H).

Spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic Acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 3-(carboxymethyl)phenyl Ester(Compound 60, General Formula 1)

[0533] A solution ofspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic Acid,8-cyclopropyl-3,4-dihydro-4,4-dimethyl-,3-(tert-butoxycarbonylmethyl)phenyl ester (Compound 59, 0.020 g, 0.04mmol) was treated with 2 mL of trifluoroacetic acid and stirred atambient temperature for 2 h. The trifluoroacetic acid was distilled offunder reduced pressure and the residue was subjected to preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phaseto afford the title compound as a white solid (0.0125 g, 62%).

[0534]¹H NMR (300 MHz, CDCl₃): δ7.99 (d, 1H, J=2.1 Hz), 7.49 (d, 1H,J=2.1 Hz), 7.36 (t, 1H, J=7.8 Hz), 7.18-7.08 (m, 3H), 3.56 (s, 2H),2.06-1.95 (m, 1H), 1.95 (s, 2H), 1.45 (s, 6H), 1.09-1.05 (m, 2H),0.96-0.84 (m, 2H), 0.74-0.65 (m, 4H).

6-Bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde(Intermediate 50)

[0535] A solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline,available in accordance with U.S. Pat. No. 5,089,509, the specificationof which is incorporated herein by reference (1.8 g, 7.5 mmol) in 10 mLof formic acid was refluxed for 3 h. The reaction mixture was thencooled to ambient temperature and poured into ice-cold saturated aqueoussodium bicarbonate solution and extracted with diethyl ether (×2). Thecombined organic phase was dried over anhydrous sodium sulfate, filteredand evaporated in vacuo to a residue which was subjected to flash columnchromatography over silica gel (230-400 mesh) using 15-25% ethyl acetatein hexane as the eluent to afford the title compound as a pale yellowsolid (1.8 g, 90%).

[0536]¹H NMR (300 MHz, CDCl₃): δ8.71 (s, 1H), 7.45 (d, 1H, J=2.2 Hz),7.28 (dd, 1H, J=2.2, 8.5 Hz), 6.98 (d, 1H, J=8.5 Hz), 3.78 (t, 2H, J=6.3Hz), 1.74 (t, 2H, J=6.3 Hz), 1.28 (s, 6H).

6-Bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline(Intermediate 51)

[0537] A stirred, cooled (0° C.) solution of6-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde(Intermediate 50, 21.8, 6.7 mmol) in anhydrous tetrahydrofuran (20 mL)under argon was treated with titanium tetra-iso-propoxide (2.15 mL, 7.39mmol) followed by 3M solution of ethyl magnesium bromide in diethylether (5.6 mL, 16.8 mmol) and the reaction mixture was then heated at50° C. overnight. It was then cooled in an ice-bath, quenched withsaturated aqueous ammonium chloride solution and extracted with diethylether (×2). The combined organic phase was dried over anhydrous sodiumsulfate, filtered over celite and evaporated in vacuo to residue whichwas subjected to flash column chromatography over silica gel (230-400mesh) using 5% ethyl acetate in hexane as the eluent to afford the titlecompound as an oil (1.2 g, 64%).

[0538]¹H NMR (300 MHz, CDCl₃): δ7.24 (d, 1H, J=2.5 Hz), 7.12 (dd, 1H,J=2.2, 8.8 Hz), 7.01 (d, 1H, J=8.8 Hz), 3.20 (t, 2H, J=6.0 Hz),2.27-2.20 (m, 1H), 1.68 (t, 2H, J=5.9 Hz), 1.24 (s, 3H), 1.23 (s, 3H),0.83-0.77 (m, 2H), 0.60-0.55 (m, 2H).

1-Cyclopropyl-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline(Intermediate 52)

[0539] Following general procedure D and using6-bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 51, 0.8 g, 2.86 mmol), (trimethylsilyl)acetylene (5 mL, 35mmol), triethyl amine (10 mL), anhydrous tetrahydrofuran,copper(I)iodide (0.080 g, 0.42 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.240 g, 0.34 mmol), thetitle compound was obtained as an oil (0.67 g, 79%).

[0540]¹H NMR (300 MHz, CDCl₃): δ7.33 (d, 1H, J=1.8 Hz), 7.22 (dd, 1H,J=2.1, 8.5 Hz), 7.06 (d, 1H, J=8.5 Hz), 3.27 (t, 2H, J=5.9 Hz),2.37-2.31 (m, 1H), 1.70 (t, 2H, J=6.0 Hz), 1.28 (s, 6H), 0.89-0.82 (m,2H), 0.66-0.60 (m, 2H), 0.28 (s, 9H).

1-Cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline:(Intermediate 53)

[0541] Following general procedure E and using1-cyclopropyl-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline(Intermediate 52, 0.40 g, 1.34 mmol), methanol and potassium carbonate(0.2 g, 1.47 mmol) followed by flash column chromatography over silicagel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, thetitle compound was obtained as an oil (0.17 g, 56%).

[0542]¹H NMR (300 MHz, CDCl₃): δ7.38 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H,J=2.1, 8.5 Hz), 7.11 (d, 1H, J=8.5 Hz), 3.30 (t, 2H, J=6.0 Hz), 3.02 (s,1H), 2.40-2.34 (m, 1H), 1.74 (t, 2H, J=6.0 Hz), 1.30 (s, 6H), 0.93-0.85(m, 2H), 0.70-0.63 (m, 2H).

4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)-benzoicAcid Ethyl Ester (Compound 61, General Formula 7)

[0543] Following general procedure F and using1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 53, 0.11 g, 0.43 mmol), ethyl-4-iodo-benzoate (Reagent A,0.11 g, 0.9 mmol), triethyl amine (3 mL), tetrahydrofuran(3 mL),copper(I)iodide (0.02 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 5-10% ethyl acetate in hexane as the eluent, the title compoundwas obtained (0.05 g, 31%).

[0544]¹H NMR (300 MHz, CDCl₃): δ7.99 (d, 2H, J=8.2 Hz), 7.54 (d, 2H,J=8.2 Hz), 7.37 (d, 1H, J=2.1 Hz), 7.26 (dd, 1H, J=2.1, 8.5 Hz), 7.10(d, 1H, J=8.8 Hz), 4.37 (q, 2H, J=7.1 Hz), 3.28 (t, 2H, J=6.0 Hz),2.40-2.33 (m, 1H), 1.71 (t, 2H, J=5.8 Hz), 1.40 (t, 3H, J=7.0 Hz), 1.27(s, 6H), 0.94-0.82 (m, 2H), 0.65-0.60 (m, 2H).

4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl-ethynyl)-benzoicAcid (Compound 62, General Formula 7)

[0545] Following general procedure L and using4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoicacid ethyl ester (Compound 61, 0.05 g, 0.13 mmol), 5 mL of ethanol and5M sodium hydroxide solution (2 mL) followed by recrystallization fromhot ethyl acetate, the title compound was obtained as a solid (0.030 g,64%).

[0546]¹H NMR (300 MHz, DMSO-d₆): δ7.92 (d, 2H, J=8.2 Hz), 7.57 (d, 2H,J=8.2 Hz), 7.33 (d, 1H, J=1.9 Hz), 7.23 (dd, 1H, J=1.9, 8.5 Hz), 7.06(d, 1H, J=8.8 Hz), 3.25 (t, 2H, J=5.8 Hz), 2.41-2.34 (m, 1H), 1.64 (t,2H, J=5.6 Hz), 1.21 (s, 6H), 0.87-0.81 (m, 2H), 0.59-0.54 (m, 2H).

[4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)phenyl]Acetic Acid Methyl Ester (Compound 63, General Formula 7)

[0547] Following general procedure F and using1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 53, 0.05 g, 0.22 mmol), methyl-4-iodo-phenyl acetate(Reagent B, 0.055 g, 0.2 mmol), triethyl amine (5 mL), tetrahydrofuran,copper(I)iodide (0.025 g, 0.13 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.75 g, 0.11 mmol)followed preparative normal phase HPLC using 10% ethyl acetate in hexaneas the mobile phase, the title compound was obtained (0.089 g, 100%).

[0548]¹H NMR (300 MHz, CDCl₃): δ7.47 (d, 2H, J=8.8 Hz), 7.45 (d, 1H,J=1.8 Hz), 7.35-7.22 (m, 2H), 7.10 (d, 2H, J=8.8 Hz), 3.70 (s, 3H), 3.63(s, 2H), 3.27 (t, 2H, J=6.0 Hz), 2.37-2.31 (m, 1H), 1.71 (t, 2H, J=6.0Hz), 1.27 (s, 6H), 0.89-0.81 (m, 2H), 0.65-0.60 (m, 2H).

[4-(1-Cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)-2-fluoro-phenyl]Acetic Acid Ethyl Ester (Compound 64, General Formula 7)

[0549] Following general procedure F and using1-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline(Intermediate 53, 0.11 g, 0.49 mmol), ethyl-2-fluoro-4-iodo-phenylacetate (Reagent C, 0.11 g, 0.9 mmol), triethyl amine (3 mL),tetrahydrofuran (3 mL), copper(I)iodide (0.06 g, 0.32 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, the title compound wasobtained (0.1 g, 51%).

[0550]¹H NMR (300 MHz, CDCl₃): δ7.34 (d, 1H, J=2.1 Hz), 7.25-7.17 (m,3H), 7.09 (d, 2H, J=8.8 Hz), 4.17 (q, 2H, J=7.1 Hz), 3.65 (s, 2H), 3.27(t, 2H, J=6.0 Hz), 2.38-2.31 (m, 1H), 1.69 (t, 2H, J=6.0 Hz), 1.27 (s,6H), 1.25 (t, 3H, J=7.1 Hz), 0.88-0.81 (m, 2H), 0.65-0.59 (m, 2H).

N-(4-Bromophenyl)-N-methyl-3-methyl-2-butenamide (Intermediate 54)

[0551] 3,3-Dimethylacryloyl chloride (3 mL, 27 mmol) was added to asolution of 4-bromo-N-methyl-aniline (4.55 g, 25 mmol) in 150 mL ofdichloromethane followed after 5 minutes by triethyl amine (5 mL, 33mmol). After 2.5 h at ambient temperature, the reaction mixture waswashed with water and the organic phase was dried over anhydrous sodiumsulfate and evaporated in vacuo to afford the title product as a brownoil in quantitative yield.

[0552]¹H-NMR (300 MHz, CDCl₃): δ1.71 (s, 3H), 2.11(s, 3H), 3.28(s, 3H),5.47(s, 1H), 7.05(d, J=8.5 Hz, 2H), 7.50(d, J=8.2 Hz, 2H).

6-Bromo-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (Intermediate55)

[0553] N-(4-bromophenyl)-N-methyl-3-methyl-2-butenamide (Intermediate54, 6.42 g, 24 mmol) was heated to 130° C. and aluminum chloride (5 g,37.4 mmol) was added in portions over 0.5 h. The reaction mixture wasstirred for 1 hour at the same temperature and then cooled to roomtemperature. Ice was added cautiously to the solid, followed by ˜200 mLof iced water. The reaction mixture was then extracted with ether (×2)and dichloromethane (×1) and the combined organic phase was dried overanhydrous magnesium sulfate and evaporated in vacuo to yield a brownsolid. The solid was treated with hexane-dichloromethane and filtered toafford 1.7 g of product. The mother liquor was evaporated and purifiedby flash column chromatography on silica gel (230-400 mesh) to afford2.9 g of the title compound as a solid (total 72%).

[0554]¹H-NMR (300 MHz, CDCl₃): δ1.29(s, 6H), 2.49(s, 2H), 3.36(s, 3H),6.87(d, J=8.2 Hz, 1H), 7.36(dd, J=2.0, 8.5 Hz, 1H), 7.39(d, J=2.0 Hz,1H).

6-Bromo-1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 56)

[0555] A stirred, cooled (−78° C.) 3M solution of ethyl magnesiumbromide in ether (8.1 mL, 24.25 mmol) under argon was treated withanhydrous tetrahydrofuran (20 mL) followed by a solution of titaniumtetra-iso-propoxide (3.15 mL, 10.2 mmol) in tetrahydrofuran (10 mL). Asolution of 6-bromo-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline(Intermediate 55, 2.6 g, 9.7 mmol) was cannulated into the reactionmixture and the solution was allowed to warm to room temperatureovernight. It was then cooled in an ice-bath, quenched with saturatedaqueous ammonium chloride solution, filtered over celite and the aqueousphase was extracted with diethyl ether (×2). The combined organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated invacuo to afford an orange oil. Flash column chromatography over silicagel (230-400 mesh) using 2-4% ethyl acetate in hexane as the eluentafforded the title compound as an oil which was ˜70% pure (1.7 g, 63%)and 0.5 g of recovered starting material.

[0556]¹H-NMR (300 MHz, CDCl₃): δ0.58(t, J=6.0 Hz, 2H), 0.91(t, J=6.0 Hz,2H), 1.35 (s, 6H), 1.70(s, 2H), 2.68 (s, 3H), 6.59 (d, J=8.8 Hz, 1H),7.16(dd, J=2.3, 8.8 Hz, 1H), 7.33(d, J=2.3 Hz, 1H).

1,4,4-Trimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 57)

[0557] Following general procedure D and using6-bromo-1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane] (Intermediate 56, 0.56 g, 2 mmol),(trimethylsilyl)acetylene (1.13 mL, 8 mmol), triethyl amine (4 mL),anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.08 g, 0.4 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.28 g, 0.4 mmol),followed by flash column chromatography over silica gel (230-400 mesh)using hexane-2% ethyl acetate in hexane as the eluent, the titlecompound was obtained as an oil (0.42 g, 70%).

[0558]¹H NMR (300 MHz, CDCl₃): δ0.023(s, 9H), 0.33(t, J=6.1 Hz, 2H),0.71(t, J=6.1 Hz, 2H), 1.10(s, 6H), 1.45(s, 2H), 2.41 (s, 3H), 6.31(d,J=8.5 Hz, 1H), 6.96 (dd, J=2.1, 8.5 Hz, 1H), 7.10(d, J=2.1 Hz, 1H).

Benzoic Acid,4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane]-6-yl)ethynyl]-ethylEster (Compound 65, General Formula 1)

[0559] Following general procedure E and using a solution of1,4,4-trimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane](Intermediate 57, 0.416 g, 1.4 mmol), methanol (10 mL), ethyl acetate (2mL) and potassium carbonate (1.08 g, mmol) a silyl deprotectedacetylenic intermediate was obtained which was used directly for thenext step (0.25 g, 79%). Following general procedure F and using part ofthe acetylenic intermediate obtained as above (0.11 g, 0.5 mmol),ethyl-4-iodo benzoate (Reagent A, 0.112 g, 0.4 mmol), triethyl amine (1mL), tetrahydrofuran (2.5 mL), copper(I)iodide (0.050 g, 0.26 mmol) andtetrakis(triphenylphosphine)palladium(0)(0.096 g, 0.17 mmol) followed byflash column chromatography over silica gel (230-400 mesh) using 8%ethyl acetate in hexane as the eluent and preparative HPLC on Partisil10 silica column using 10% ethyl acetate in hexane as the mobile phase,the title compound was obtained as a yellow oil (0.048 g, 26%).

[0560]¹H-NMR (300 MHz, CDCl₃): δ0.60 (t, J=6.1 Hz, 2H), 0.99(t, J=6.1Hz, 2H), 1.37(s, 6H), 1.42(t, J=7.0 Hz, 3H), 1.73(s, 2H), 2.68(s, 3H),4.40 (q, J=7.0 Hz, 2H), 6.61(d, J=8.8 Hz, 1H), 7.28 (dd, J=2.1, 8.5 Hz,1H), 7.42 (d, J=2.1 Hz, 1H), 7.57(d, J=8.2 Hz, 2H), 8.01(d, J=8.2 Hz,2H).

Benzoic Acid,4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane]-6-yl)ethynyl]-(Compound 66, General Formula 1)

[0561] Following general procedure I and using benzoic acid,4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1′-cyclopropane]-6-yl)ethynyl]-ethyl ester (Compound 65, 0.03 g, 0.08mmol), ethanol (2 mL), tetrahydrofuran (2 mL) and 1M aqueous sodiumhydroxide solution (1 mL), the title compound was obtained as a yellowsolid (0.020 g, 67%).

[0562]¹H-NMR (300 MHz, CD₃COCD₃): δ0.60 (t, J=5.8 Hz, 2H), 1.03(t, J=5.8Hz, 2H), 1.34(s, 6H), 1.74(s, 2H), 2.69(s, 3H), 6.60(d, J=8.5 Hz, 1H),7.23 (dd, J=2.0, 8.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.58(d, J=8.2 Hz,2H), 8.01(d, J=8.2 Hz, 2H).

[0563] Esterification Methods:

[0564] Method A:

[0565] The carboxylic acid was combined with a solution of the desiredalcohol and concentrated sulfuric acid (20 to 1 v/v) and the resultingmixture or solution (0.75 to 1.0 M) heated to reflux overnight. Thesolution was cooled to room temperature, diluted with Et₂O, and washedwith H₂O, saturated aqueous NaHCO₃, and saturated aqueous NaCl beforebeing dried over MgSO₄. Concentration of the dry solution under reducedpressure afforded the desired carboxylic ester of sufficient purity tobe used directly in the next reaction.

[0566] Method B:

[0567] To a solution (0.67 to 1.0M) of the carboxylic acid in acetonewas added 1.1 equivalents of the desired alkyl halide and 1.0equivalents of solid potassium carbonate. The resulting mixture washeated to reflux for 2 h and then allowed to stir at room temperatureovernight. The mixture was filtered and the filtrate concentrated underreduced pressure. The product was isolated from the residue by columnchromatography using silica gel as the solid phase.

[0568] Method C:

[0569] A solution (1M) of the carboxylic acid in thionyl chloride washeated at reflux until analysis of a reaction aliquot by IR spectroscopyshowed the absence of the aryl carboxylic acid carbonyl band ( 1705-1680cm⁻¹). The solution was cooled to room temperature and concentratedunder reduced pressure to give the crude acyl chloride.

[0570] The acyl chloride was dissolved in CH₂Cl₂ and the resultingsolution (0.5 to 0.75M) treated with 1.1 equivalents the desired alcoholand 2.0 equivalents of pyridine. After stirring overnight at roomtemperature the solution was diluted with Et₂O and washed with H₂O, 10%aqueous HCl, saturated aqueous NaHCO₃, and saturated aqueous NaCl beforebeing dried over Na₂SO₄. Concentration of the dry solution under reducedpressure followed by column chromatography afforded the desired ester.

[0571] General Procedure 1 (Preparation of Enol Ethers)

[0572] A solution (0.35 M) of the aryl ester in anhydrous THF was cooledto 0° C. and treated with 1.0 equivalents of Tebbe's Reagent([μ-chloro-μ-methylene[bis(cyclopentadienyl)titanium]-dimethylaluminum]0.5 M in toluene). After 30 minutes the solution was warmed to roomtemperature and stirred for 30 minutes before being carefully added to a0.1 N NaOH solution at 0° C. This mixture was treated with hexanes andthe solids removed by filtration through a pad of Celite. The solidswere washed with hexanes and the filtrate passed through a second pad ofCelite to remove any newly formed solids. The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure. The desired enol etherwas isolated from the residue by column chromatography using 1-2% ofEt₃N added to the eluant. (note: prolonged exposure of the product tothe column can result in hydrolysis and formation of the correspondingmethyl ketone.)

[0573] General Procedure 2 (Cyclopropanation of the Enol Ethers):

[0574] To a solution (0.3 M) of the enol ether in anhydrous Et₂O wasadded 2.0 equivalent of Et₂Zn (as a solution in hexanes) and 2.0equivalents of CH₂I₂. The resulting solution was heated to reflux untilanalysis of a reaction aliquot (by TLC or ¹H NMR) indicated that all ofthe starting enol ether had been consumed. (note: Additional equalamounts of Et₂Zn and CH₂I₂ can be added to drive the reaction tocompletion.) Upon cooling to room temperature the reaction was carefullyquenched by the addition of saturated aqueous NH₄Cl. The resultingmixture is extracted with Et₂O and the combined organic layers washedwith H₂O and saturated aqueous NaCl before being dried over Na₂SO₄ andconcentrated under reduced pressure. The product is isolated from theresidue by column chromatography.

1-Bromo-4-(1-methoxyvinyl)-benzene: (Intermediate 58)

[0575] Using General Procedure 1; methyl 4-bromo-benzoate (600.0 mg,2.78 mmols), and 5.6 mL of Tebbe's Reagent (794.0 mg, 2.78 mmols)afforded 420.0 mg (70%) of the title compound as a colorless oil aftercolumn chromatography (100% hexanes).

[0576]¹H NMR (CDCl₃) δ: 7.48-7.45 (4H, m), 4.64 (1H, d, J=2.9 Hz), 4.23(1H, d, J=2.9 Hz), 3.73 (3H, s).

1-Bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59)

[0577] Using General Procedure 2; 1-bromo-4-(1-methoxyvinyl)-benzene(Intermediate 58, 410.0 mg, 1.92 mmols), Et₂Zn (711.3 mg, 5.76 mmols),and CH₂I₂ (1.54 g, 5.76 mmols) in 4.0 mL Et₂O afforded 300.0 mg (69%) ofthe title compound as a colorless oil after chromatography (0-3%EtOAc-hexanes).

[0578]¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz),3.21 (3H, s), 1.19 (2H, m), 0.94 (2H, m).

[4-(1-Methoxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate60)

[0579] Using General Procedure D;1-bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59, 300.0 mg,1.32 mmol) in triethylamine (4 mL) and anhydrous tetrahydrofuran (4 mL)was treated with copper(I)iodide (93.0 mg, 0.13 mmol) and then spargedwith argon for 5 minutes. Trimethylsilyl acetylene (1.39 g, 14.2 mmols)was then added followed by dichlorobis(triphenylphosphine)palladium(II)(93.0 mg, 0.13 mmol). The resulting reaction mixture was heated to 70°C. for 60 h. The title compound (286.0 mg, 90%) was isolated bychromatography (0-3% EtOAc-hexanes).

[0580]¹H NMR (CDCl₃) δ: 7.35 (2H, d, J=7.2 Hz), 7.14 (2H, d, J=7.2 Hz),3.14 (3H, s), 1.14 (2H, m), 0.88 (2H, m), 0.17 (9H, s).

1-Ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61)

[0581] Using General Procedure E;[4-(1-methoxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate60, 285.0 mg, 1.18 mmols) in methanol (10 mL) was treated with potassiumcarbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambienttemperature. The crude alkyne (220 mg, 100%) was used directly in thenext reaction.

[0582]¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz),3.23 (3H, s), 3.06 (1H, s), 1.22 (2H, m), 0.98 (2H, m).

Ethyl 4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67,General Formula 2)

[0583] Using General Procedure F;1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg,0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) intriethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0mg (90%) of the title compound as an orange solid.

[0584]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.8 Hz),7.52 (2H, d, J=8.2 Hz), 7.28 (2H, d, J=8.8 Hz), 4.39 (2H, q, J=7.1 Hz),3.25 (3H, s), 1.40 (3H, t, J=7.1 Hz), 1.23 (2H, m), 1.00 (2H, m).

Methyl {4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 68, General Formula 2)

[0585] Using General Procedure F;1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 120.0 mg,0.56 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 154.0 mg, 0.56mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (35.0mg, 0.19 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-8% EtOAc-hexanes) afforded 140.0mg (78%) of the title compound as an orange solid.

[0586]¹H NMR (CDCl₃) δ: 7.50 (4H, d, J=8.1 Hz), 7.28 (4H, d, J=8.1 Hz),3.76 (3H, s), 3.64 (2H, s), 3.25 (3H, s), 1.22 (2H, m), 0.99 (2H, m).

4-[4-(1-Methoxycyclopropyl)-phenylethynyl]-benzoic Acid (Compound 69,General Formula 2)

[0587] Using General Procedure I; a solution of ethyl4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0mg, 0.34 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treatedwith NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) andstirred overnight at room temperature. Work-up afforded 85.0 mg (86%) ofthe title compound as an orange solid.

[0588]¹H NMR (CDCl₃) δ: 8.05 (2H), 7.66 (2H), 7.56 (2H, d, J=8.5 Hz),7.35 (2H, d, J=8.6 Hz), 3.22 (3H, s), 1.21 (2H, m), 1.01 (2H, m).

{4-[4-(1-Methoxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid(Compound 70, General Formula 2)

[0589] Using General Procedure I; a solution of methyl{4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound68, 100.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueoussolution) and stirred overnight at room temperature. Work-up afforded80.0 mg (84%) of the title compound as an orange solid.

[0590] hu 1H NMR (CDCl₃) δ: 7.49 (4H), 7.27 (4H), 3.66 (2H, s), 3.25(3H, s), 1.22 (2H, m), 0.99 (2H, m).

Isopropyl 4-bromobenzoate (Intermediate 62)

[0591] Using General Esterification Procedure A; 4-bromobenzoic acid(1.50 g, 7.46 mmols) was combined with isopropyl alcohol to give 1.76 g(97%) of the title compound as a colorless oil.

[0592]¹H NMR (CDCl₃) δ: 7.90 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz),5.24 (1H, septet, J=6.2 Hz), 1.37 (6H, d, J=6.2 Hz).

1-Bromo-4-(1-isopropoxyvinyl)-benzene (Intermediate 63)

[0593] Using General Procedure 1; isopropyl 4-bromobenzoate(Intermediate 62, 780.0 mg, 3.20 mmols) and 6.4 mL of Tebbe's Reagent(910.7 mg, 3.20 mmols) afforded 328.0 mg (43%) of the title compound asa colorless oil after column chromatography (100% hexanes).

[0594]¹H NMR (CDCl₃) δ: 7.46 (4H, m), 4.66 (1H, d, J=2.6 Hz), 4.40 (1H,septet, J=6.2 Hz), 4.21 (1H, d, J=2.6 Hz), 1.34 (6H, d, J=6.2 Hz).

1-Bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64)

[0595] Using General Procedure 2; 1-bromo-4-(1-isopropoxyvinyl)-benzene(Intermediate 63, 328.0 mg, 1.36 mmols), Et₂Zn (335.9 mg, 2.72 mmols),and CH₂I₂ (728.0 mg, 2.72 mmols) in 4.0 mL Et₂O afforded 240.0 mg (70%)of the title compound as a colorless oil after chromatography (3%EtOAc-hexanes).

[0596]¹H NMR (CDCl₃) δ: 7.43 (2H, d, J=8.5 Hz), 7.27 (2H, d, J=8.5 Hz),3.70 (1H, septet, J=6.2 Hz), 1.18 (2H, m), 1.06 (6H, d, J=6.2 Hz), 0.91(2H, m).

[4-(1-Isopropoxycyclopropyl)-phenylethynyl]-trimethylsilane(Intermediate 65)

[0597] Using General Procedure D;1-bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64, 240.0 mg,0.94 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(18.0 mg, 0.094 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed bydichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 0.094 mmol). Theresulting reaction mixture was heated to 70° C. for 5 days. The titlecompound (250.0 mg, 98%) was isolated by chromatography (0-3%EtOAc-hexanes) as an orange oil.

[0598]¹H NMR (CDCl₃) δ: 7.41 (2H, d, J=7.9 Hz), 7.31 (2H, d, J=7.9 Hz),3.70 (1H, septet, J=6.2 Hz), 1.18 (2H, m), 1.05 (6H, d, J=6.2 Hz), 0.93(2H, m), 0.94 (9H, s).

1-Ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66)

[0599] Using General Procedure E;[4-(1-isopropoxycyclopropyl)-phenylethynyl]-trimethylsilane(Intermediate 65, 260.0 mg, 0.96 mmol) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (220 mg, 100%) was used directlyin the next reaction.

[0600]¹H NMR (CDCl₃) δ: 7.45 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz),3.72 (1H, septet, J=6.2 Hz), 3.06 (1H, s), 1.20 (2H, m), 1.07 (6H, d,J=6.2 Hz), 0.95 (2H, m).

Ethyl 4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound71, General Formula 2)

[0601] Using General Procedure F;1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 114.0mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63mmol) in triethylamine (8 mL) was treated with copper(I)iodide (36.0 mg,0.19 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 151.0mg (76%) of the title compound as an orange solid.

[0602]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=7.6 Hz), 7.58 (2H, d, J=7.6 Hz),7.50 (2H, d, J=7.8 Hz), 7.39 (2H, d, J=7.8 Hz), 4.39 (2H, q, J=7.1 Hz),3.74 (1H, septet, J=6.2 Hz), 1.40 (3H, t, J=7.1 Hz), 1.22 (2H, m), 1.08(6H, d, J=6.2 Hz), 0.97 (2H, m).

Methyl {4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 72, General Formula 2)

[0603] Using General Procedure F;1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 95.0 mg,0.45 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 131.0 mg, 0.45mmol) in triethylamine (6 mL) was treated with copper(I)iodide (30.0 mg,0.16 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-8% EtOAc-hexanes) afforded 110.0mg (70%) of the title compound as an orange oil.

[0604]¹H NMR (CDCl₃) δ: 7.20 (4H), 7.08 (2H, d, J=7.0 Hz), 6.97 (2H, d,J=7.9 Hz), 3.45 (1H, septet, J=6.2 Hz), 3.41 (3H, s), 3.35 (2H, s), 0.91(2H, m), 0.79 (6H, d, J=6.2 Hz), 0.68 (2H, m).

4-[4-(1-Isopropoxycyclopropyl)-phenylethynyl]-benzoic acid (Compound 73,General Formula 2)

[0605] Using General Procedure I; a solution of ethyl4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71,110.0 mg, 0.32 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 89.0 mg(88%) of the title compound as a yellow solid.

[0606]¹H NMR (CDCl₃) δ: 8.06 (2H, d, J=8.2 Hz), 7.66 (2H, d, J=8.2 Hz),7.55 (2H, d, J=8.2 Hz), 7.46 (2H, d, J=8.2 Hz), 3.73 (1H, septet, J=6.2Hz), 1.18 (2H, m), 1.04 (6H, d, J=6.2 Hz), 0.99 (2H, m).

{4-[4-(1-Isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetic Acid(Compound 74, General Formula 2)

[0607] Using General Procedure I; a solution of methyl{4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound72, 80.0 mg, 0.23 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 48.0 mg(56%) of the title compound as a solid.

[0608]¹H NMR (CDCl₃) δ: 7.20 (2H, d, J=8.2 Hz), 7.19 (2H, d, J=8.8 Hz),7.09 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.2 Hz), 3.46 (1H, septet, J=6.2Hz), 3.37 (2H, s), 0.92 (2H, m), 0.79 (6H, d, J=6.2 Hz), 0.67 (2H, m).

Benzyl 4-bromobenzoate (Intermediate 67)

[0609] Using General Esterification Method B; 4-bromobenzoic acid (2.01g, 10.0 mmols), benzyl bromide (1.89 g, 11.1 mmols), and K₂CO₃ (1.40 g,10.0 mmols) afforded 2.33 g (80%) of the title compound as a colorlesssolid after column chromatography (3-10% EtOAc-hexanes).

[0610]¹H NMR (CDCl₃) δ: 7.89 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz),7.43-7.31 (5H), 5.33 (2H, s).

1-Bromo-4-(1-benzyloxyvinyl)-benzene (Intermediate 68)

[0611] Using General Procedure 1; benzyl 4-bromobenzoate (Intermediate67, 920.0 mg, 3.16 mmols) and 6.3 mL of Tebbe's Reagent (897.0 mg, 3.16mmols) afforded 640.0 mg (70%) of the title compound after columnchromatography (100% hexanes).

[0612]¹H NMR (CDCl₃) δ: 7.55-7.35 (9H), 4.95 (2H, s), 4.73 (1H, d, J=2.9Hz), 4.34 (1H, d, J=2.9 Hz).

1-Bromo-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 69)

[0613] Using General Procedure 2; 1-bromo-4-(1-benzyloxyvinyl)-benzene(Intermediate 68, 280.0 mg, 0.97 mmol), Et₂Zn (247.0 mg, 2.0 mmols), andCH₂I₂ (536.0 mg, 2.0 mmols) in 2.0 mL Et₂O afforded 159.0 mg (53%) ofthe title compound as a colorless solid after chromatography (2-5%EtOAc-hexanes).

[0614]¹H NMR (CDCl₃) δ: 7.49-7.24 (9H), 4.41 (2H, s), 1.29 (2H, m), 1.00(2H, m).

[4-(1-Benzyloxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate70)

[0615] Using General Procedure D;1-bromo-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 69, 160.0 mg,0.53 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes.Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed bydichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). Theresulting reaction mixture was heated to 70° C. for 5 d. The titlecompound (150.0 mg, 83%) was isolated by chromatography (0-3%EtOAc-hexanes) as a pale-yellow oil.

[0616] hu 1H NMR (CDCl₃) δ: 7.21 (3H, m), 7.09-7.01 (6H, m), 4.18 (2H,s), 1.07 (2H, m), 0.79 (2H, m), 0.02 (9H, s).

1-Ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71)

[0617] Using General Procedure E;[4-(1-benzyloxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate70, 150.0 mg, 0.47 mmols) in methanol (6 mL) was treated with potassiumcarbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambienttemperature. The crude alkyne (115 mg, 100%) was used directly in thenext reaction.

[0618]¹H NMR (CDCl₃) δ: 7.67-7.50 (2H, d, J=8.2 Hz), 7.34-7.26 (7H, m),4.43 (2H, s), 3.07 (1H, s), 1.32 (2H, m), 1.04 (2H, m).

Ethyl 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound75, General Formula 2)

[0619] Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg,0.24 mmol) and ethyl-4-iodo benzoate (Reagent A, 72.0 mg, 0.26 mmol) intriethylamine (4 mL) was treated with copper(I)iodide (17.0 mg, 0.09mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (61 mg, 0.09 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 85.0 mg(91%) of the title compound as an orange oil.

[0620]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.62-7.54 (4H, m),7.39-7.26 (7H, m), 4.47 (2H, s), 4.40 (2H, q, J=7.1 Hz), 1.42 (3H, t,J=7.1 Hz), 1.36 (2H, m), 1.07 (2H, m).

Methyl {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate(Compound 76, General Formula 2)

[0621] Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg,0.20 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 66.0 mg, 0.24mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg,0.08 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-7% EtOAc-hexanes) afforded 64.0 mg(81%) of the title compound as a yellow oil.

[0622]¹H NMR (CDCl₃) δ: 7.52-7.47 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H,s), 3.70 (3H, s), 3.64 (2H,s), 1.32 (2H, m), 1.06 (2H, m).

4-[-(1-Benzyloxycyclopropyl)-phenylethynyl]-benzoic acid (Compound 77,General Formula 2)

[0623] Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0mg, 0.20 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treatedwith NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) andstirred overnight at room temperature. Work-up afforded 65.0 mg (89%) ofthe title compound as a solid.

[0624]¹H NMR (CDCl₃) δ: 7.97 (2H, d, J=8.5 Hz), 7.67 (2H, d, J=8.7 Hz),7.58 (2H, d, J=8.5 Hz), 7.41-7.28 (7H, m), 4.44 (2H, s), 1.33 (2H, m),1.12 (2H, m).

{4-[4-(1-Benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetic Acid(Compound 78, General Formula 2)

[0625] Using General Procedure I; a solution of methyl{4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 35.0 mg(81%) of the title compound as a pale-yellow solid.

[0626] hu 1H NMR (CDCl₃) δ: 7.49 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H,s), 3.66 (2H, s), 1.32 (2H, m), 1.05 (2H, m).

Benzyl 4-bromo-2-methylbenzoate (Intermediate 72)

[0627] Using General Esterification Method C; 2-methyl-4-bromo-benzoicacid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL SOCl₂. Theresulting solution concentrated under reduced pressure and the crudeacyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) andpyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%)after work-up and column chromatography (2-5% EtOAc-hexanes) as acolorless oil.

[0628]¹H NMR (CDCl₃) δ: 7.81 (1H, d, J=8.5 Hz), 7.41-7.33 (7H, m), 5.32(2H, s), 2.57 (3H, s).

4-Bromo-1-(1-benzyloxyvinyl)-2-methylbenzene (Intermediate 73)

[0629] Using General Procedure 1; benzyl 4-bromo-2-methylbenzoate(Intermediate 72, 840.0 mg, 2.77 mmols) and 5.4 mL of Tebbe's Reagent(788.0 mg, 2.77 mmols) afforded 640.0 mg (76%) of the title compoundafter column chromatography (100% hexanes).

[0630]¹H NMR (CDCl₃) δ: 7.38-7.19 (8H, m), 4.88 (2H, s), 4.45 (1H, d,J=2.6 Hz), 4.25 (2H, d, J=2.6 Hz), 2.35 (3H, s).

4-Bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74)

[0631] Using General Procedure 2;4-bromo-1-(1-benzyloxyvinyl)-2-methyl-benzene (Intermediate 73, 400.0mg, 1.32 mmols), Et₂Zn (325.0 mg, 2.63 mmols), and CH₂I₂ (704.0 mg, 2.63mmols) in 4 mL Et₂O afforded 380.0 mg (90%) of the title compound as acolorless oil after chromatography (2-5% EtOAc-hexanes).

[0632] hu 1H NMR (CDCl₃) δ: 7.42-7.20 (8H, m), 4.31 (2H, s), 2.58 (3H,s), 1.25 (2H, m), 0.94 (2H, m).

[4-(1-Benzyloxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 75)

[0633] Using General Procedure D;4-bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74,320.0 mg, 1.00 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (19.0 mg, 0.1 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.05mmol). The resulting reaction mixture was heated to 70° C. for 5 d. Thetitle compound (300.0 mg, 89%) was isolated by chromatography (0-2%EtOAc-hexanes).

[0634]¹H NMR (CDCl₃) δ: 7.34-7.13 (8H, m), 4.24 (2H, s), 2.52 (3H, s),1.20 (2H, m), 0.88 (2H, m), 0.25 (9H, s).

4-Ethynyl-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 76)

[0635] Using General Procedure E;[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 75, 300.0 mg, 0.95 mmols) in methanol (6 mL) was treatedwith potassium carbonate (120.0 mg, 0.87 mmol) and stirred overnight atambient temperature. The crude alkyne (185 mg, 79%) was used directly inthe next reaction.

[0636] hu 1H NMR (CDCl₃) δ: 7.37-7.16 (8H, m), 4.27 (2H, s), 3.07 (1H,s), 2.55 (3H, s), 1.21 (2H, m), 0.92 (2H, m).

Ethyl 4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate(Compound 79, General Formula 2)

[0637] Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76,90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg,0.12 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 68.0 mg(54%) of the title compound.

[0638]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz),7.33-7.16 (8H, m), 4.39 (2H, q, J=7.1 Hz), 4.29 (2H, s), 2.57 (3H, s),1.40 (3H, t, J=7.1 Hz), 1.22 (2H, m), 0.93 (2H, m).

Methyl{4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 80, General Formula 2)

[0639] Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76,90.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 95.0mg, 0.34 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 90.0 mg(71%) of the title compound as a pale-yellow oil.

[0640]¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.32-7.16 (10H, m), 4.28(2H, s), 3.70 (3H, s), 3.64 (2H, s) 2.56 (3H, s), 1.22 (2H, m), 0.92(2H, m).

4-[4-(1-Benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoic acid(Compound 81, General Formula 2)

[0641] Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound79, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution)and stirred overnight at room temperature. Work-up afforded 48.0 mg(76%) of the title compound as a solid.

[0642]¹H NMR (CDCl₃) δ: 8.10 (2H, d, J=8.1 Hz), 7.63 (2H, d, J=8.1 Hz),7.44-7.16 (8H, m), 4.29 (2H, m), 2.58 (3H, s), 1.24 (2H, m), 0.94 (2H,m).

{4-[4-(1-Benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-aceticAcid (Compound 82, General Formula 2)

[0643] Using General Procedure I; a solution of methyl{4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 80, 75.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 30.0 mg (40%) of the title compound.

[0644]¹H NMR (CDCl₃) δ: 7.51 (2H, d,=8.2 Hz), 7.42 (1H, s), 7.33-7.17(9H, m), 4.36 (2H, s), 3.67 (2H, s), 2.57 (3H, s), 1.23 (2H, m), 0.94(2H, m).

Isopropyl 3-methyl-4-bromobenzoate (Intermediate 77)

[0645] Using General Esterification Procedure A; 4-bromo-2-methylbenzoicacid (1.6 g, 7.4 mmols) was combined with isopropyl alcohol to give 1.5g (79%) of the title compound as a colorless oil.

[0646]¹H NMR (CDCl₃) δ: 7.76 (1H, d, J=8.2 Hz), 7.40 (1H, d, J=7.4 Hz),7.37 (1H, dd, J=1.4, 8.2 Hz), 5.23 (1H, septet, J=6.2 Hz), 2.57 (3H, s),1.37 (6H, d, J=6.2 Hz).

4-Bromo-1-(1-isopropoxyvinyl)-2-methyl-benzene (Intermediate 78)

[0647] Using General Procedure 1; isopropyl 2-methyl-4-bromobenzoate(Intermediate 77, 800.0 mg, 3.11 mmols) and 6.2 mL of Tebbe's Reagent(885.2 mg, 3.11 mmols) afforded 595.0 mg (75%) of the title compound asa colorless oil after column chromatography (100% hexanes).

[0648]¹H NMR (CDCl₃) δ: 7.31-7.25 (2H, m), 7.16 (1H, d, J=8.2 Hz), 4.34(1H, septet, J=6.0 Hz), 4.31 (1H, d, J=2.1 Hz), 4.18 (1H, d, J=2.1 Hz),2.33 (3H, s), 1.31 (6H, d, J=6.0 Hz).

4-Bromo-1-(1-isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 79)

[0649] Using General Procedure 2;4-bromo-1-(1-isopropoxyvinyl)-2-methyl-benzene (Intermediate 78, 389.0mg, 1.53 mmols), Et₂Zn (376.6 mg, 3.05 mmols), and CH₂I₂ (817.0 mg, 3.05mmols) in 3.0 mL Et₂O afforded 340.0 mg (84%) of the title compound as acolorless oil after chromatography (3% EtOAc-hexanes).

[0650]¹H NMR (CDCl₃) δ: 7.33 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=2.3, 8.2Hz), 7.13 (1H, d, J=8.2 Hz), 3.57 (1H, septet, J=6.1 Hz), 2.49 (3H, s),1.00 (2H, m), 0.97 (6H, d, J=6.1 Hz), 0.82 (2H, m).

[4-(1-Isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 80)

[0651] Using General Procedure D;4-bromo-1-(1-isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 79,250.0 mg, 0.95 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (19.0 mg, 0.10 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.1mmol). The resulting reaction mixture was heated to 70° C. for 5 d. Thetitle compound (250.0 mg, 91%) was isolated by chromatography (0-3%EtOAc-hexanes).

[0652]¹H NMR (CDCl₃) δ: 7.32-7.17 (3H, m), 3.56 (1H, septet, J=6.2 Hz),2.48 (3H, s), 1.00 (2H, m), 0.95 (6H, d, J=6.2 Hz), 0.83 (2H, m), 0.24(9H, s).

4-Ethynyl-1-(1isopropoxycyclopropyl)-2-methyl-benzene (Intermediate 81)

[0653] Using General Procedure E;[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 80, 250.0 mg, 0.87 mmol) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (180 mg, 98%) was used directly inthe next reaction.

[0654]¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.23 (2H, m), 3.57 (1H, septet,J=6.2 Hz), 3.05 (1H, s), 2.50 (3H, s), 1.11 (2H, m), 0.96 (6H, d, J=6.2Hz), 0.83 (2H, m).

Ethyl 4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate(Compound 83, General Formula 2)

[0655] Using General Procedure F;4-ethynyl-1-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81,80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg,0.13 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (91 mg, 0.13 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 75.0 mg(56%) of the title compound as an orange solid.

[0656]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz),7.39 (1H, s), 7.29-7.20 (2H, m), 4.39 (2H, q, J=7.1 Hz), 3.60 (1H,septet, J=6.2 Hz), 1.40 (3H, t, J=7.1 Hz), 1.13 (2H, m), 0.97 (6H, d,J=6.2 Hz), 0.87 (2H, m).

Methyl{4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 84, General Formula 2)

[0657] Using General Procedure F;1-ethynyl-4-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81,100.0 mg, 0.47 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 129.0mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide(30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (110 mg, 0.16 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 120.0mg (71%) of the title compound.

[0658]¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.5 Hz), 7.36 (1H, s), 7.29-7.22(4H, m), 3.70 (3H, s), 3.63 (2H, s), 3.60 (1H, septet, J=6.2 Hz), 2.52(3H, s), 1.09 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.86 (2H, m).

4-[4-(1-Isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoic Acid(Compound 85, General Formula 2)

[0659] Using General Procedure I; a solution of ethyl4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate(Compound 83, 60.0 mg, 0.17 mmol) in ethanol (2 mL) and tetrahydrofuran(2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded38.0 mg (69%) of the title compound as a colorless solid.

[0660]¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.5 Hz), 7.66 (2H, d, J=8.5Hz), 7.42 (1H, s), 7.35 (2H, m), 3.59 (1H, septet, J=6.2 Hz), 2.52 (3H,s), 1.07 (2H, m), 0.93 (6H, d, J=6.2 Hz), 0.88 (2H, m).

{4-[4-(1-Isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-aceticAcid (Compound 86, General Formula 2)

[0661] Using General Procedure I; a solution of methyl{4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 60.0 mg (62%) of the title compound as a colorless solid.

[0662]¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=7.6 Hz), 7.36 (1H, s), 7.25 (4H,m), 3.65 (2H, s), 3.60 (1H, septet, J=6.2 Hz), 2.51 (3H, s), 1.12 (2H,m), 0.97 (6H, d, J=6.2 Hz), 0.86 (2H, m).

2,2-Dimethylpropyl 2-methyl-4-bromobenzoate (Intermediate 82)

[0663] Using General Esterification Method C; 2-methyl-4-bromo-benzoicacid (1.82 g, 8.47 mmols) was refluxed for 3 h with 10 mL SOCl₂. Theresulting solution was concentrated under reduced pressure and the crudeacyl chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols)and pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g,68%) after work-up and column chromatography (2-5% EtOAc-hexanes) as acolorless oil.

[0664]¹H NMR (CDCl₃) δ: 7.81 (1H, d, J=8.2 Hz), 7.42 (1H, d, J=2.0 Hz),7.39 (1H, dd, J=2.0, 8.2 Hz), 3.99 (2H, s), 2.60 (3H, s), 1.03 (9H, s).

4-Bromo-1-[1-(2,2-dimethylpropyloxy)-vinyl]-2-methyl-benzene(Intermediate 83)

[0665] Using General Procedure 1; 2,2-dimethylpropyl2-methyl-4-bromobenzoate (Intermediate 82, 820.0 mg, 2.87 mmols) and 5.8mL of Tebbe's Reagent (817.0 mg, 2.87 mmols) afforded 800.0 mg (98%) ofthe title compound as a colorless oil after column chromatography (100%hexanes).

[0666]¹H NMR (CDCl₃) δ: 7.32 (1H, d, J=2.0 Hz), 7.28 (1H, dd, J=2.0, 8.2Hz), 7.18 (1H, d, J=8.2 Hz), 4.27 (1H, d, J=2.1 Hz), 4.10 (1H, d, J=2.1Hz), 3.43 (2H, s), 2.33 (3H, s), 0.98 (9H, s).

4-Bromo-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 84)

[0667] Using General Procedure 2;4-bromo-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 83, 400.0 mg, 1.43 mmols), Et₂Zn (353.2 mg, 2.86 mmols),and CH₂I₂ (760.0 mg, 2.86 mmols) in 3.0 mL Et₂O afforded 370.0 mg (87%)of the title compound as a colorless oil after chromatography (3%EtOAc-hexanes).

[0668] hu 1H NMR (CDCl₃) δ: 7.36 (1H, s),7.27 (1H, d, J=8.5 Hz), 7.09(1H, d, J=7.9 Hz), 2.86 (2H, s), 2.52 (3H, s), 1.08 (2H, m), 0.83 (2H,m), 0.80 (9H, s).

[4-[1-[1-(2,2-Dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]]-trimethylsilane(Intermediate 84a)

[0669] Using General Procedure D;4-bromo-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 84, 255.0 mg, 0.86 mmol) in triethylamine (8 mL) wastreated with copper(I)iodide (17.0 mg, 0.09 mmol) and then sparged withargon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) wasthen added followed by dichlorobis-(triphenylphosphine)palladium(II)(63.0 mg, 0.09 mmol). The resulting reaction mixture was heated to 70°C. for 5 d. The title compound (220.0 mg, 81%) was isolated bychromatography (1-2% EtOAc-hexanes).

[0670]¹H NMR (CDCl₃) δ: 7.30 (1H, s), 7.21 (1H, d, J=7.6 Hz), 7.12 (1H,d, J=8.6 Hz), 2.80 (2H, s), 2.47 (3H, s), 1.05 (2H, m), 0.82 (2H, m),0.75 (9H, s), 0.24 (9H, s).

4-Ethynyl-1- [1-(2,2-dimethylpropyloxy)-cyclopropyl]-2-methyl-benzene(Intermediate 85)

[0671] Using General Procedure E;[4-[1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]]-3-methyl-phenylethynyl]-trimethylsilane(Intermediate 84a, 220.0 mg, 0.83 mmol) in methanol (10 mL) was treatedwith potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight atambient temperature. The crude alkyne (155 mg, 76%) was used directly inthe next reaction.

[0672]¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.24 (1H, d, J=7.1 Hz), 7.15 (1H,d, J=7.1 Hz), 3.04 (1H, s), 2.83 (2H, s), 2.49 (3H, s), 1.06 (2H, m),0.83 (2H, m), 0.76 (9H, s).

Ethyl4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate(Compound 87, General Formula 2)

[0673] Using General Procedure F;4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene(Intermediate 85, 75.0 mg, 0.31 mmol) and ethyl-4-iodo benzoate (ReagentA, 86.0 mg, 0.31 mmol) in triethylamine (5 mL) was treated withcopper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)-palladium(II) (78 mg, 0.11mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 60.0 mg(50%) of the title compound as an orange solid.

[0674]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz),7.38 (1H, s), 7.30 (1H, dd, J=1.1, 8.0 Hz), 7.20 (1H, d, J=8.0 Hz), 4.38(2H, q, J=7.1 Hz), 2.84 (2H, s), 2.52 (3H, s), 1.40 (3H, t, J=7.1 Hz),1.07 (2H, m) 0.84 (2H, m), 0.77 (9H, s).

Methyl{4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 88, General Formula 2)

[0675] Using General Procedure F;4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene(Intermediate 85, 75.0 mg, 0.31 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 86.0 mg, 0.31 mmol) in triethylamine (6 mL) was treated withcopper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (78 mg, 0.11 mmol)was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0mg (83%) of the title compound.

[0676]¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=7.9 Hz), 7.36-7.24 (4H, m), 7.18(1H, d, J=7.9 Hz), 3.70 (3H, s), 3.63 (2H, s), 2.84 (2H, s), 2.51 (3H,s), 1.07 (2H, m), 0.83 (2H, m), 0.77 (9H, s).

4-[4-[1-(2,2-Dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoicacid (Compound 89, General Formula 2)

[0677] Using General Procedure I; a solution of ethyl4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate(Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 24.0 mg (43%) of the title compound as a colorless solid.

[0678]¹H NMR (CDCl₃) δ: 8.06 (2H, d, J=7.9 Hz), 7.65 (2H, d, J=7.9 Hz),7.42 (1H, s), 7.33 (2H, m), 2.89 (2H, s), 2.53 (3H, s), 1.07 (2H, m),0.90 (2H, m), 0.77 (9H, s).

{4-[4-[1-(2,2-Dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-aceticacid (Compound 90, General Formula 2)

[0679] Using General Procedure I; a solution of methyl{4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate(Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 49.0 mg (53%) of the title compound as a colorless solid.

[0680]¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.36 (1H, s), 7.27 (3H,m), 7.18 (1H, d, J=7.9 Hz), 3.66 (2H, s), 2.84 (2H, s), 2.51 (3H, s),1.07 (2H, m), 0.83 (2H, m), 0.77 (9H, s).

Benzyl 4-bromo-2-ethyl-benzoate (Intermediate 86)

[0681] Using General Esterification Method B; 4-bromo-2-ethyl-benzoicAcid (0.98 g, 4.25 mmols), benzyl bromide (0.80 g, 4.68 mmols), andK₂CO₃ (0.64 g, 4.68 mmols) afforded 1.0 g (74%) of the title compoundafter column chromatography (0-3% EtOAc-hexanes).

[0682]¹H NMR (CDCl₃) δ: 7.76 (1H, d, J=8.5 Hz), 7.41-7.33 (7H, m), 5.32(2H, s), 2.95 (2H, q, J=7.6 Hz), 1.20 (3H, t, J=7.6 Hz).

4-Bromo-1-(1-benzyloxyvinyl)-2-ethyl-benzene (Intermediate 87)

[0683] Using General Procedure 1; benzyl 4-bromo-2-ethylbenzoate(Intermediate 86, 1.20 g, 3.78 mmols) and 7.6 mL of Tebbe's Reagent(1.08 g, 3.78 mmols) afforded 800.0 mg (66%) of the title compound aftercolumn chromatography (100% hexanes).

[0684]¹H NMR (CDCl₃) δ: 7.37-7.17 (8H, m), 4.88 (2H, s), 4.43 (1H, d,J=2.1 Hz), 4.25 (1H, d, J=2.1 Hz), 2.71 (2H, q, J=7.6 Hz), 1.18 (3H, t,J=7.6 Hz).

4-Bromo-1-(1-benzyloxycyclopropyl)-2-ethyl-benzene (Intermediate 88)

[0685] Using General Procedure 2;4-bromo-1-(1-benzyloxyvinyl)-2-ethyl-benzene (Intermediate 87, 330.0 mg,1.04 mmols), Et₂Zn (257.0 mg, 2.08 mmols), and CH₂I₂ (557.0 mg, 2.08mmols) in 4 mL Et₂O afforded 241.0 mg (70%) of the title compound as acolorless oil after chromatography (2-5% EtOAc-hexanes).

[0686]¹H NMR (CDCl₃) δ: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.00 (2H, q,J=7.6 Hz), 1.29-1.21 (5H, m), 0.90 (2H, m).

[4-(1-Benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 89)

[0687] Using General Procedure D;4-bromo-1-(l-benzyloxycyclopropyl)-2-ethyl-benzene (Intermediate 88,220.0 mg, 0.66 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (14.0 mg, 0.07 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (50.0 mg, 0.07mmol). The resulting reaction mixture was heated to 70° C. for 5 d. Thetitle compound was isolated by chromatography (0-2% EtOAc-hexanes).

[0688]¹H NMR (CDCl₃) δ: 7.41-7.13 (8H, m), 4.24 (2H, s), 2.98 (2H, q,J=7.6 Hz), 1.25 (3H, t, J=7.6 Hz), 1.20 (2H, m), 0.90 (2H, m), 0.26 (9H,s).

4-Ethynyl-1-(1-benzyloxycyclopropyl)-2-ethyl-benzene (Intermediate 90)

[0689] Using General Procedure E;[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 89, 240 mg, 0.69 mmol) in methanol (6 mL) was treated withpotassium carbonate (10.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (190 mg, 99%) was used directly inthe next reaction.

[0690]¹H NMR (CDCl₃) δ: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.08 (1H, s),3.01 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.6 Hz), 1.22 (2H, m), 0.92 (2H,m).

Ethyl 4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate(Compound 91, General Formula 2)

[0691] Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90,90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg,0.11 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0mg (72%) of the title compound.

[0692]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=7.9 Hz), 7.59 (2H, d, J=7.9 Hz),7.49 (1H, s), 7.36-7.16 (7H, m), 4.38 (2H, q, J=7.1 Hz), 4.28 (2H, s),3.04 (2H, q, J=7.6 Hz), 1.40 (3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.6 Hz),1.23 (2H, m), 0.94 (2H, m).

Methyl{4-[4-1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 92, General Formula 2)

[0693] Using General Procedure F;1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90,107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0mg, 0.39 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 130.0mg (79%) of the title compound as a pale-yellow oil.

[0694] hu 1H NMR (CDCl₃) δ: 7.49 (3H, m), 7.32-7.16 (9H, m), 4.28 (2H,s), 3.71 (3H, s), 3.64 (2H, s), 3.03 (2H, q, J=7.6 Hz), 1.32-1.23 (5H,m), 0.94 (2H, m).

4-[4-(1-Benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoic Acid(Compound 93, General Formula 2)

[0695] Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound91, 100.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up andpurification by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded the titlecompound as a colorless solid.

[0696]¹H NMR (CDCl₃) δ: 8.10 (2H, d, J=8.5 Hz), 7.64 (2H, d, J=8.5 Hz),7.50 (1H, s), 7.35-7.16 (7H, m), 4.29 (2H, s), 3.04 (2H, q, J=7.6 Hz),1.30 (3H, t, J=7.6 Hz), 1.25 (2H, m), 0.95 (2H, m).

{4-[4-(1-Benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-aceticAcid (Compound 94, General Formula 2)

[0697] Using General Procedure I; a solution of methyl{4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-up andpurification by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded the titlecompound.

[0698]¹H NMR (CDCl₃) δ: 7.49 (3H, m), 7.31-7.16 (9H, m), 4.28 (2H, s),3.66 (2H, s), 3.02 (2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz), 1.23 (2H,m), 0.94 (2H, m).

Isopropyl 2-ethyl-4-bromobenzoate (Intermediate 91)

[0699] Using General Esterification Procedure A; 4-bromo-2-ethyl-benzoicacid (2.25 g, 9.9 mmols) was combined with isopropyl alcohol to give thetitle compound as a colorless oil after column chromatography (2%EtOAc-hexanes).

[0700]¹H NMR (CDCl₃) δ: 7.69 (1H, d, J=8.5 Hz), 7.41 (1H, s), 7.36 (1H,d, J=8.5 Hz), 5.23 (1H, septet, J=6.2 Hz), 2.95 (2H, q, J=7.6 Hz), 1.37(6H, d, J=6.2 Hz), 1.23 (3H, t, J=7.6 Hz).

4-Bromo-1-(1-isopropoxyvinyl)-2-ethyl-benzene (Intermediate 92)

[0701] Using General Procedure 1; isopropyl 2-ethyl-4-bromobenzoate(Intermediate 91, 1.21 g, 4.46 mmols) and 8.9 mL of Tebbe's Reagent(1.27 g, 4.46 mmols) afforded 570.0 mg (75%) of the title compound aftercolumn chromatography (100% hexanes).

[0702]¹H NMR (CDCl₃) δ: 7.36 (1H, d, J=2.0 Hz), 7.28 (1H, dd, J=2.0, 8.0Hz), 7.17 (1H, d, J=8.0 Hz), 4.39 (1H, septet, J=6.2 Hz), 4.31 (1H, d,J=2.1 Hz), 4.26 (1H, d, J=2.1 Hz), 2.73 (2H, q, J=7.6 Hz), 1.35 (6H, d,J=6.2 Hz), 1.24 (3H, t, J=7.6 Hz).

4-Bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93)

[0703] Using General Procedure 2;4-bromo-1-(1-isopropoxyvinyl)-2-ethyl-benzene (Intermediate 92, 570.0mg, 2.11 mmols), Et₂Zn (521.0 mg, 4.22 mmols), and CH₂I₂ (1.13 g, 4.22mmols) in 7.0 mL Et₂O afforded 500.0 mg (85%) of the title compound as acolorless oil after chromatography (3% EtOAc-hexanes).

[0704]¹H NMR (CDCl₃) δ: 7.39 (1H, d, J=2.1 Hz), 7.25 (1H, dd, J=2.1, 8.1Hz), 7.15 (1H, d, J=8.1 Hz), 3.59 (1H, septet, J=6.2 Hz), 2.97 (2H, q,J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz), 1.11 (2H, m), 0.97 (6H, d, J=6.2 Hz),0.83 (2H, m).

[4-(1-Isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 94)

[0705] Using General Procedure D;4-bromo-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 93,300.0 mg, 1.07 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (20.0 mg, 0.11 mmol) and then sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 mg, 0.11mmol). The resulting reaction mixture was heated to 70° C. for 5 d. Thetitle compound (320.0 mg, 99%) was isolated by chromatography (0-2%EtOAc-hexanes) as an orange oil.

[0706]¹H NMR (CDCl₃) δ: 7.37-7.21 (3H, m), 3.56 (1H, septet, J=6.2 Hz),2.96 (2H, q, J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz), 1.10 (2H, m), 0.94 (6H,d, J=6.2 Hz), 0.84 (2H, m), 0.25 (9H, s).

4-Ethynyl-1-(1-isopropoxycyclopropyl)-2-ethyl-benzene (Intermediate 95)

[0707] Using General Procedure E;[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-trimethylsilane(Intermediate 94, 330.0 mg, 1.10 mmols) in methanol (10 mL) was treatedwith potassium carbonate (150.0 mg, 1.10 mmol) and stirred overnight atambient temperature. The crude alkyne (238 mg, 95%) was used directly inthe next reaction.

[0708]¹H NMR (CDCl₃) δ: 7.40-7.22 (3H, m), 3.59 (1H, septet, J=6.2 Hz),3.07 (1H, s), 2.97 (2H, q, J=7.6 Hz), 1.28 (3H, t, J=7.6 Hz), 1.12 (2H,m), 0.96 (6H, d, J=6.2 Hz), 0.85 (2H, m).

Ethyl 4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate(Compound 95, General Formula 2)

[0709] Using General Procedure F;4-ethynyl-1-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95,108.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 130.0 mg, 047mmol) in triethylamine (5 mL) was treated with copper(I)iodide (30.0 mg,0.16 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (110 mg, 0.16 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 125.0mg (71%) of the title compound as an oil.

[0710]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.2 Hz), 7.59 (2H, d, J 8.2 Hz),7.46 (1H, s), 7.33 -7.26 (2H, m), 4.39 (2H, q, J=7.1 Hz), 3.62 (1H,septet, J=6.2 Hz), 3.01 (2H, q, J 7.6 Hz), 1.41 (3H, t, J=7.1 Hz), 1.31(3H, t, J=7.1 Hz), 1.14 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.88 (2H, m).

Methyl{4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 96, General Formula 2)

[0711] Using General Procedure F;1-ethynyl-4-(1-isopropoxycyclopropyl)-3-ethyl-benzene (Intermediate 95,130.0 mg, 0.57 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 157.0mg, 0.57 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc-hexanes) afforded 150.0mg (70%) of the title compound as an orange oil.

[0712] hu 1H NMR (CDCl₃) δ: 7.50-7.44 (3H, m), 7.27 (4H, m), 3.70 (3H,s), 3.64 (2H, s), 3.62 (1H, septet, J=6.2 Hz), 3.00 (2H, q, J=7.6 Hz),1.30 (3H, t, J=7.6 Hz), 1.13 (2H, m), 0.97 (6H, d, J=6.2 Hz), 0.87 (2H,m).

4-[4-(1-Isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoic Acid(Compound 97, General Formula 2)

[0713] Using General Procedure I; a solution of ethyl4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound95, 110.0 mg, 0.29 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up andisolation by HPLC (partisil 10-pac, 10% H₂O/CH₃CN) afforded the titlecompound as a colorless solid.

[0714]¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.2 Hz), 7.67 (2H, d, J=8.2Hz), 7.49 (1H, s), 7.40-7.34 (2H, m), 3.61 (1H, septet, J=6.2 Hz), 3.01(2H, q, J=7.6 Hz), 1.29 (3H, t, J=7.6 Hz), 1.08 (2H, m), 0.93 (6H, d,J=6.2 Hz), 0.88 (2H, m).

{4-[4-(1-Isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-aceticacid (Compound 98, General Formula 2)

[0715] Using General Procedure I; a solution of methyl{4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate(Compound 96, 156.0 mg, 0.41 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-up andisolation by HPLC (partisil 10-pac, 10% H₂O/CH₃CN) afforded 85.0 mg(57%) of the title compound.

[0716]¹H NMR (CDCl₃) δ: 7.54-7.48 (3H, m), 7.34-7.27 (4H, m), 3.68 (2H,s), 3.66 (1H, septet, J=6.2 Hz), 3.03 (2H, q, J=7.6 Hz), 1.33 (2H, t,J=7.6 Hz), 1.17 (2H, m), 1.01 (6H, d, J=6.2 Hz), 0.90 (2H, m).

(4-Bromo-3-isopropyl-phenoxy)-triisopropyl-silane (Intermediate 96)

[0717] To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols)and imidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was addedchloro-triisopropylsilane (946.0 mg, 4.90 mmols). After stirringovernight at room temperature the solution was diluted with H₂O andextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (MgSO₄) and concentratedunder reduced pressure. The title compound, 1.30 g (92%), was isolatedby column chromatography (1-2% EtOAc-hexanes) as a colorless oil.

[0718]¹H NMR (CDCl₃) δ: 7.34 (1H, d, J=8.5 Hz), 6.81 (1H, d, J=2.9 Hz),6.59 (1H, dd, J=2.9, 8.5 Hz), 3.31 (1H, septet, J=7.0 Hz), 1.33-1.21(3H, m), 1.24 (6H, d, J=7.0 Hz), 1.13 (18H, d, J=7.0 Hz).

Ethyl 2-isopropyl-4-triisopropylsilanyloxy-benzoate (Intermediate 97)

[0719] To a solution of(4-bromo-3-isopropyl-phenoxy)-triisopropyl-silane (Intermediate 96, 1.3g, 3.8 mmols) in 15 mL Et₂O cooled to −78° C. was added 4.9 mL oftert-butyllithium in pentane (532.0 mg, 8.3 mmols; 1.7 M). Afterstirring for 30 minutes ethyl chloroformate (832.0 mg, 7.8 mmols) wasadded. The resulting solution was warmed to room temperature andquenched by the addition of saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc and the combined organic layers dried (MgSO₄)concentrated under reduced pressure and the residue chromatographed (4%EtOAc-hexanes) to give 1.09 g (85%) of the title compound as a colorlessoil.

[0720]¹H NMR (CDCl₃) δ: 7.72 (1H, d, J=8.5 Hz), 6.87 (1H, d, J=2.3 Hz),6.69 (1H, dd, J=2.3, 8.5 Hz), 3.88 (1H, septet; J=7.1 Hz), 4.30 (2H, q,J=7.1 Hz), 1.36 (3H, t, J=7.1 Hz), 1.31-1.17 (9H, m), 1.09 (18H).

[4-(1-Ethoxyvinyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 98)

[0721] Using General Procedure 1; ethyl2-isopropyl-4-triisopropylsilanyloxy-benzoate (Intermediate 97, 450.0mg, 1.34 mmols) and 2.0 mL of Tebbe's Reagent (398.0 mg, 1.40 mmols)afforded the title compound after column chromatography (100% hexanes).

[0722]¹H NMR (CDCl₃) δ: 7.11 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=2.3 Hz),6.63 (1H, dd, J=2.3, 8.2 Hz), 4.23 (1H, d, J=1.7 Hz), 4.10 (1H, d, J=1.7Hz), 3.86 (2H, q, J=7.0 Hz), 3.16 (1H, septet, J=7.0 Hz), 1.35 (3H, t,J=7.1 Hz), 1.28-1.19 (3H, m), 1.19 (6H, d, J=7.0 Hz), 1.11 (18H).

[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 99)

[0723] Using General Procedure 2;[4-(1-ethoxyvinyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 98, 300.0 mg, 0.83 mmols), Et₂Zn (325.0 mg, 2.63 mmols),and CH₂I₂ (704.0 mg, 2.63 mmols) in 5.0 mL Et₂O afforded 270.0 mg (86%)of the title compound as a colorless oil after chromatography (0.5-2.5%EtOAc-hexanes).

[0724]¹H NMR (CDCl₃) δ: 7.06 (1H, d, J=8.2 Hz), 6.81 (1H, d, J=2.6 Hz),6.59 (1H, dd, J=2.6, 8.2 Hz), 3.76 (1H, septet, J=7.0 Hz), 3.25 (2H, q,J=7.0 Hz), 1.30-1.20 (3H, m), 1.19 (6H, d, J=7.0 Hz), 1.15 (2H, m), 1.10(18H), 1.02 (2H, t, J=7.0 Hz), 0.82 (2H, m).

4-(1-Ethoxycyclopropyl)-3-isopropyl-phenol (Intermediate 100)

[0725] To a solution of[4-(1-ethoxycyclopropyl)-3-isopropyl-phenoxy]-triisopropyl-silane(Intermediate 99, 360.0 mg, 0.96 mmol) in 3 mL THF at 0° C. was addedtetrabutylammonium fluoride (625.0 mg, 2.39 mmols, 2.4 mL of a 1 Msolution in THE). The solution was stirred at 0° C. for 30 minutes andthen quenched by the addition of H₂O. The mixture was extracted withEtOAc and the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound (180 mg, 86%) was isolated from the residueby column chromatography (4-10% EtOAc-hexanes) as a colorless solid.

[0726]¹H NMR (CDCl₃) δ: 7.13 (1H, d, J=8.2 Hz), 6.79 (1H, d, J=2.6 H),6.57 (1H, dd, J=2.6, 8.2 Hz), 5.48 (1H, s), 3.79 (1H, septet, J=7.0 Hz),3.32 (2H, q, J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 1.12 (2H, m), 1.05 (3H,t, J=70 Hz), 0.84 (2H, m).

4-(1-Ethoxycyclopropyl)-3-isopropyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 101)

[0727] A solution of 4-(1-ethoxycyclopropyl)-3-isopropyl-phenol(Intermediate 100, 172.0 mg, 0.78 mmol) in 5 mL of CH₂Cl₂ was cooled to0° C. and to it was added2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (321.0 mg,0.82 mmol) and triethylamine (240.0 mg, 2.4 mmols). The resultingsolution was warmed to room temperature and stirred overnight. Thereaction was quenched by the addition of H₂O and the mixture extractedwith EtOAc and the combined organic layers were washed with 10% aqueousHCl, saturated aqueous NaHCO₃, H₂O, and saturated aqueous NaCl. Thesolution was dried (MgSO₄) and concentrated under reduced pressure. Thetitle compound was isolated by column chromatography (2-4%EtOAc-hexanes) as a colorless oil, 240.0 mg, 87%.

[0728]¹H NMR (CDCl₃) δ: 7.31 (1H, d, J=8.6 Hz), 7.18 (1H, d, J=2.6 Hz),7.00 (1H, dd, J=2.6, 8.6 Hz), 3.87 (1H, septet, J=7.0 Hz), 2.38 (2H, q,J=7.0 Hz), 1.24 (6H, d, J=7.0 Hz), 1.15 (2H, m), 1.04 (3H, t, J=7.0 Hz),0.86 (2H), m).

[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane(Intermediate 102)

[0729] Using General Procedure D;4-(1-ethoxycyclopropyl)-3-isopropyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 mmol)in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05mmol). The resulting reaction mixture was heated to 95° C. for 5 d. Thetitle compound, 200.0 mg (99%), was isolated by chromatography (0-2%EtOAc-hexanes) as an orange oil.

[0730]¹H NMR (CDCl₃) δ: 7.43 (1H, d, J=1.7 Hz), 7.25 (1H, dd, J=1.7, 7.9Hz), 7.16 (1H, d, J=7.9 Hz), 3.80 (1H, septet, J=6.8 Hz), 3.26 (2H, q,J=7.0 Hz), 1.24 (6H, d, J=6.8 Hz), 1.24-1.10 (2H, m), 1.03 (3H, t, J=7.0Hz), 0.87 (2H, s), 0.26 (9H, s).

1-(1-Ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103)

[0731] Using General Procedure E;[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane(Intermediate 102, 210.0 mg, 0.70 mmol) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne was used directly in the nextreaction.

[0732]¹H NMR (CDCl₃) δ: 7.47 (1H, d, J=1.7 Hz), 7.23 (1H, dd, J=1.7, 7.6Hz), 7.19 (1H, d, J=7.6 Hz), 3.80(1H, septet, J=7.0 Hz), 3.27 (1H, q,J=7.0 Hz), 3.07 (1H, s), 1.23 (6H, d, J=7.0 Hz), 1.13 (2H, m), 1.03 (3H,t, J=7.0 Hz), 0.85 (2H, m).

Ethyl 4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate(Compound 99, General Formula 2)

[0733] Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103,50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg,0.07 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (1-2% EtOAc-hexanes) afforded 28.0 mg(34%) of the title compound.

[0734]¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz),7.51 (1H, d J=1.7 Hz), 7.28 (1H, dd, J=1.7, 7.9 Hz), 7.21 (1H, d, J=7.9Hz), 4.38 (2H, q, J=7.1 Hz), 3.83 (1H, septet, J=6.7 Hz), 3.29 (2H, q,J=7.0 Hz), 1.40 (3H, t, J=7.1 Hz), 1.26 (6H, d, J=6.7 Hz), 1.14 (2H, m),1.04 (3H, t, J=7.0 Hz), 0.87 (2H, m).

Methyl{4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Compound 100, General Formula 2)

[0735] Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103,120.0 mg, 0.52 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 150.0mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc-hexanes) afforded 140.0mg (71%) of the title compound as a pale-yellow oil.

[0736]¹H NMR (CDCl₃) δ: 7.53 (3H, m), 7.31-7.23 (4H, m), 3.86 (1H,septet, J=6.7 Hz), 3.73 (3H, s), 3.67 (2H, s), 3.33 (2H, q, J=7.0 Hz),1.30 (6H, d, J=6.7 Hz), 1.15 (2H, m), 1.08 (3H, t, J=7.0 Hz), 0.90 (2H,m).

4-[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoic acid(Compound 101, General Formula 2)

[0737] Using General Procedure I; A solution of ethyl4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound99, 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) wastreated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 24 mg (92%)the title compound as a pale-yellow solid.

[0738]¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.2 Hz), 7.66 (2H, d, J 8.2Hz), 7.58 (1H, s), 7.33 (2H, m), 3.87 (1H, m), 2.27 (2H, q, J=7.0 Hz),1.26 (6, d, J=6.7 Hz), 1.09 (2H, m), 0.99 (3H, t, J=7.0 Hz), 0.88 (2H,m).

{4-[4-(1-Ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-aceticAcid (Compound 102, General Formula 2)

[0739] Using General Procedure I; a solution of methyl{4-[4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Compound 100, 130.0 mg, 0.35 mmol) in ethanol (5 mL) andtetrahydrofuran (5 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0mL of a 1N aqueous solution) and stirred at 50° C. for 4 h. Work-up andisolation by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded 88.0 mg(70%) of the title compound.

[0740]¹H NMR (CDCl₃) δ: 7.50 (3H, m), 7.28-7.19 (4H, m), 3.82 (1H, m),3.65 (2H, s), 3.29 (2H, q, J=7.0 Hz), 1.25 (6H, d, J=6.7 Hz), 1.14 (2H,m), 1.04 (3H, t, J=7.0 Hz), 0.86 (2H, m).

4-Bromo-3-tert-butylphenol (Intermediate 104)

[0741] To a mixture of 3-tert-butyl-methoxy benzene (1.00 g, 6.09 mmols)in CCl₄ (20 mL), molecular sieves, and silica gel was addedN-bromosuccinimide (1.19 g, 6.70 mmols). This mixture was stirred at 55°C. for 48 h. The resulting mixture was cooled to room temperature,filtered to remove the solids, and the filtrate diluted with EtOAc. Thissolution was washed with H₂O, 10% aqueous HCl, H₂O, saturated aqueousNaHCO₃ and saturated aqueous NaCl before being dried (MgSO₄) andconcentrated under reduced pressure. Column chromatography (2.5%EtOAc-hexanes) afforded 1.15 g (78%) of a 3 to 1 mixture of1-bromo-2-tert-butyl methoxy benzene and 1-bromo-2-methoxy-4-tert-butylbenzene as a colorless oil.

[0742] A solution of the isomeric methoxy compounds in 10 mL of CH₂Cl₂was cooled to 0° C. and treated with a solution (18.5 mL) of BBr₃ inCH₂Cl₂ (4.63 g, 18.5 mmols). After 10 minutes the solution was warmed toroom temperature, stirred for 1 h, and then quenched with H₂O. Themixture was extracted with EtOAc and the combined organic layers washedwith saturated aqueous NaCl, dried (MgSO₄), and concentrated underreduced pressure. The title compound was isolated, 1.17 g (59%), bycolumn chromatography (2.5-5% EtOAc-hexanes).

[0743]¹H NMR (CDCl₃) δ: 7.39 (1H, d, J=8.5 Hz), 6.96 (1H, d, J=2.9 Hz),6.54 (1H, dd, J=2.9, 8.5 Hz), 1.46 (9H, s).

(4-Bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105)

[0744] To a solution of 4-bromo-3-tert-butylphenol (Intermediate 104,1.17 g, 5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMFwas added chloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirringovernight at room temperature the solution was diluted with H₂O andextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (MgSO₄) and concentratedunder reduced pressure. The title compound, 1.80 g (92%), was isolatedby column chromatography (0-1.5% EtOAc-hexanes) as a colorless oil.

[0745]¹H NMR (CDCl₃) δ: 7.38 (1H, d, J=8.0 Hz), 6.97 (1H, d, J=2.9 Hz),6.56 (1H, dd, J=2.9, 8.5 Hz), 1.47 (9H, s), 1.29-1.24 (3H, m), 1.09(18H, d, J=6.7 Hz).

Ethyl 2-tert-butyl-4-triisopropylsilanyloxy-benzoate (Intermediate 106)

[0746] To a solution of(4-bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105,1.00 g, 2.60 mmols) in 15 mL Et₂O cooled to −78° C. was added 3.6 mL oftert-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). Afterstirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) wasadded. The resulting solution was warmed to room temperature andquenched by the addition of saturated aqueous NH₄Cl. The mixture wasextracted with EtOAc and the combined organic layers dried (MgSO₄)concentrated under reduced pressure The residue was chromatographed(2-5% EtOAc-hexanes) to give 1.23 g (88%) of the title compound as acolorless oil.

[0747]¹H NMR (CDCl₃) δ: 7.24 (1H, d, J=8.2 Hz), 6.97 (1H, d, J=2.6 Hz),6.69 (1H, dd, J=2.6, 8.2 Hz), 4.33 (2H, q, J=7.1 Hz), 1.39 (9H, s), 1.37(3H, t, J=7.1 Hz), 1.29-1.21 (3H, m), 1.10 (18H, d, J=6.7 Hz).

[4-(1-Ethoxyvinyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 107)

[0748] Using General Procedure 1; ethyl2-tert-butyl-4-triisopropylsilanyloxy-benzoate (Intermediate 106, 1.30g, 3.44 mmols) and 7.2 mL of Tebbe's Reagent (1.03 g, 3.61 mmols) werereacted. The reaction required 7 days at room temperature to go tocompletion. The standard work-up afforded 1.29 g (78%) of the titlecompound after column chromatography (1-2% EtOAc-hexanes).

[0749]¹H NMR (CDCl₃) δ: 7.05 (1H, d, J=8.2 Hz), 6.94 (1H, d, J=2.6 Hz),6.63 (1H, dd, J=2.6, 8.2 Hz), 4.20 (1H, d, J=1.7 Hz), 4.08 (1H, d, J=1.7Hz), 3.83 (2H, q, J=7.1 Hz), 1.37 (9H, s), 1.36 (3H, t, J=7.1 Hz),1.27-1.20 (3H, m), 1.10 (18H, d, J=6.7 Hz).

[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 108)

[0750] Using General Procedure 2;[4-(1-ethoxyvinyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 107, 320.0 mg, 0.85 mmols), Et₂Zn (325.0 mg, 2.63 mmols),and CH₂I₂ (704.0 mg, 2.63 mmols) in 5.0 mL Et₂O afforded 257.0 mg (66%)of the title compound as a colorless oil after chromatography (1-2.5%EtOAc-hexanes).

[0751]¹H NMR (CDCl₃) δ: 7.24 (1H, d, J=8.5 Hz), 7.06 (1H, d, J=2.6 Hz),6.60 (1H, dd, J=2.6, 8.5 Hz), 3.24 (2H, q, J=7.1 Hz), 1.50 (9H, s),1.29-1.21 (3H, m), 1.11 (18H, d, J=6.7 Hz), 1.04 (3H, t, J=7.1 Hz).

4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenol (Intermediate 109)

[0752] To a solution of[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane(Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 0° C. was addedtetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1 Msolution in THF). The solution was stirred at 0° C. for 30 minutes andthen quenched by the addition of H₂O. The mixture was extracted withEtOAc and the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound (400 mg, 88%) was isolated from the residueby column chromatography (4-10% EtOAc-hexanes) as a colorless solid.

[0753]¹H NMR (CDCl₃) δ: 7.29 (1H, d, J=8.2 Hz), 7.01 (1H, d, J=2.6 Hz),6.57 (1H, dd, J=2.6, 8.2 Hz), 3.29 (2H, q, J=7.1 Hz), 1.59 (9H, s),1.08-1.04 (7H, m).

4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 110)

[0754] A solution of 4-(1-ethoxycyclopropyl)-3-tert-butyl-phenol(Intermediate 109, 400.0 mg, 1.71 mmol) in 10 mL of CH₂Cl₂ was cooled to0° C. and to it was added2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (705.0 mg,1.79 mmol) and triethylamine (522.0 mg, 5.1 mmols). The resultingsolution was warmed to room temperature and stirred overnight. Thereaction was quenched by the addition of H₂O and the mixture extractedwith EtOAc and the combined organic layers were washed with 10% aqueousHCl, saturated aqueous NaHCO₃, H₂O, and saturated aqueous NaCl. Thesolution was dried (MgSO₄) and concentrated under reduced pressure. Thetitle compound was isolated by column chromatography (2-4%EtOAc-hexanes) as a colorless oil, 542.0 mg (87%).

[0755]¹H NMR (CDCl₃) δ: 7.48 (1H, d, J=8.5 Hz), 7.39 (1H, d, J=2.6 Hz),7.01 (1H, dd, J=2.6, 8.5 Hz), 3.26 (2H, q, J=7.1 hz), 1.52 (9H, s), 1.12(2H, bs), 1.08-1.04 (5H, m).

[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-trimethylsilane(Intermediate 111)

[0756] Using General Procedure D;4-(1-ethoxycyclopropyl)-3-tert-butyl-phenyl1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 mmol)in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06mmol). The resulting reaction mixture was heated to 95° C. for 18 hours.The title compound, 215.0 mg (96%), was isolated by chromatography (0-2%EtOAc-hexanes) as an orange oil.

[0757]¹H NMR (CDCl₃) δ: 7.63 (1H, d, J=1.7 Hz), 7.32 (1H, d, J=7.9 Hz),7.19 (1H, dd, J=1.7, 7.9 Hz), 3.24 (2H, q, J=7.1 Hz), 1.51 (9H, s), 1.10(2H, bs), 1.06-1.01 (5H, m), 0.25 (9H, s).

1-(1-Ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112)

[0758] Using General Procedure E;[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-trimethylsilane(Intermediate 111, 215.0 mg, 0.69 mmol) in methanol (10 mL) was treatedwith potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight atambient temperature. The crude alkyne, 169 mg, was used directly in thenext reaction.

[0759]¹H NMR (CDCl₃) δ: 7.68 (1H, d, J=1.8 Hz), 7.36 (1H, d, J=7.9 Hz),7.23 (1H, dd, J=1.8, 7.9 Hz), 3.26 (2H, q, J=7.1 Hz), 3.06 (1H, s), 1.51(9H, s), 1.11 (2H, bs), 1.07-1.02 (5H, m).

Ethyl 4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate(Compound 103, General Formula 2)

[0760] Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112,70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg,0.01 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (1-2% EtOAc-hexanes) afforded 70.0 mg(73%) of the title compound.

[0761]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.8 Hz), 7.72 (1H, d, J=1.7 Hz),7.59 (2H, d, J=8.8 Hz), 7.40 (1H, d, J=7.9 Hz), 7.28 (1H, dd, J=1.7, 7.9Hz), 4.39 (2H, q, J=7.1 Hz), 3.28 (2H, q, J=7.1 Hz), 1.55 (9H, s), 1.40(3H, t, J=7.1 Hz), 1.12 (2H, bs), 1.08-1.04 (5H, m).

Methyl{4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-acetate(Compound 104, General Formula 2)

[0762] Using General Procedure F;1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112,95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc-hexanes) afforded 100.0mg (72%) of the title compound.

[0763]¹H NMR (CDCl₃) δ: 7.70 (1H, d, J=1.5 Hz), 7.50 (2H, d, J=7.9 Hz),7.38 (1H, d, J=7.9 Hz), 7.27 (3H, m), 3.70 (3H, s), 3.64 (2H, s), 3.28(2H, q, J=7.1 Hz), 1.54 (9H, s), 1.12 (2H, bs), 1.08-1.03 (5H, m).

4-[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoic Acid(Compound 105, General Formula 2)

[0764] Using General Procedure I; a solution of ethyl4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-benzoate(Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2Naqueous solution) and stirred overnight at room temperature. Work-upafforded 40 mg (62%) the title compound as a pale-yellow solid.

[0765]¹H NMR (d₆-acetone) δ: 8.06 (2H, d, J=8.7 Hz), 7.76 (1H, d, J=1.8Hz), 7.67 (2H, d, J=8.7 Hz), 7.50 (1H, d, J=7.9 Hz), 7.33 (1H, dd,J=1.8, 7.9 Hz), 3.28 (2H, q, J=7.3 Hz), 1.54 (9H, s), 1.13 (2H, bs),1.10 (2H, m), 1.02 (3H, t, J=7.31 Hz).

{4-[4-(1-Ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-aceticAcid (Compound 106, General Formula 2)

[0766] Using General Procedure I; a solution of methyl{4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-acetate(Compound 104, 100.0 mg, 0.26 mmol) in ethanol (4 mL) andtetrahydrofuran (4 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 3.0mL of a 2N aqueous solution) and stirred at 50° C. for 4 h. Work-up andisolation by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded 70.0 mg(73%) of the title compound.

[0767]¹H NMR (CDCl₃) δ: 7.73 (1H, d, J=1.3 Hz), 7.53 (2H, d, J=7.9 Hz),7.41 (1H, d, J=7.9 Hz), 7.28 (3H, m), 3.69 (2H, s), 3.31 (2H, q, J=7.1Hz), 1.56 (9H, s), 1.15 (2H, bs), 1.11-1.05 (5H, m).

1-(4-Bromophenyl)-cyclopropanecarbonitrile (Intermediate 113)

[0768] To a 50% aqueous NaOH solution (40.0 g, wt/wt) was added benzyltriethylammonium chloride (1.0 g, 4.4 mmols), 4-bromobenzonitrile (19.6g, 0.10 mol), and 1,2-dibromoethane (56.4 g, 0.30 mol). The mixture wasstirred overnight at room temperature and then diluted with 100 mL ofH₂O. This mixture was extracted with EtOAc and the combined extractswere washed with saturated aqueous NaHS₂O₃, H₂O, and saturated aqueousNaCl before being dried (MgSO₄) and concentrated under reduced pressure.Bulb-to-bulb distillation afforded 18.8 g (85%) of the title compound asa colorless solid.

[0769]¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz),1.75 (2H, dd, J=5.2, 7.6 Hz), 1.39 (2H, dd, J=5.2, 7.6 Hz).

1-(4-Bromophenyl)-cyclopropanecarboxylic Acid (Intermediate 114)

[0770] To a solution of KOH (6.06 g, 0.11 mol) in 10 mL of H₂O was added40 mL of ethylene glycol and 1-(4-bromophenyl)-cyclopropanecarbonitrile(Intermediate 113, 10.0 g, 0.45 mol). This solution was heated to135-140° C. for 4 h, cooled to room temperature, and then poured into amixture of 100 mL ice and 10% aqueous HCl. The resulting mixture wasallowed to stand overnight at 5° C., the solid was collected byfiltration and washed with H₂O. The colorless solid was dried underreduced pressure to give 10.6 g (97%) of the title compound.

[0771]¹H NMR (CDCl₃) δ: 7.43 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz),1.68 (2H, dd, J=4.0, 7.1 Hz), 1.24 (2H, dd, J=4.0, 7.1 Hz).

Tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115)

[0772] A solution of 1-(4-bromophenyl)-cyclopropanecarboxylic Acid(Intermediate 114, 2.32 g, 9.62 mmols), diphenylphosphoryl azide (2.65g, 9.62 mmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL tert-BuOH(distilled from Na°) was heated to reflux for 17 h. The solution wasconcentrated under reduced pressure and the residue dissolved in EtOAcand washed with 5% aqueous HCl, H₂O, saturated aqueous NaHCO₃, andsaturated aqueous NaCl before being dried over MgSO₄. Concentration ofthe dry solution under reduced pressure and column chromatography (5-10%EtOAc-hexanes) afforded 2.01 g (67%) of the title compound as acolorless solid.

[0773]¹H NMR (CDCl₃) δ: 7.39 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.3 Hz),5.35 (1H, bs), 1.43 (9H, s), 1.26 (2H, m), 1.17 (2H, m).

1-(4-Bromophenyl)-cyclopropalamine (Intermediate 116)

[0774] To a solution of tert-butyl[1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115, 1.08 g,3.40 mmols) in 20 mL MeOH and 20 mL THF was added 20 mL of 3M aqueousHCl. The solution was warmed to 35° C. for 3 hours and then stirred for17 h at 25° C. The reaction was quenched by adjusting the pH of thesolution to 12 with 3M aqueous NaOH. The mixture was extracted with Et₂Oand the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound 613 mg (85%) was used without furtherpurification.

[0775]¹H NMR (CDCl₃) δ: 7.43 (2H, d, J=8.3 Hz), 7.17 (2H, d, J=8.3 Hz),1.89 (2H, bs), 1.07 (2H, m), 0.95 (2H, m).

N-[1-(4-bromophenyl)-cyclopropyl]-propionamide (Intermediate 117)

[0776] To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate116, 84 mg, 0.4 mmol) in 4 mL CH₂Cl₂ at room temperature was addedpropionyl chloride (43.0 mg, 0.47 mmol) and pyridine (56.0 mg, 0.71mmol). After stirring 17 hours at room temperature the reaction wasquenched by the addition of H₂O and extracted with EtOAc. The combinedextracts were washed with 10% aqueous HCl, saturated aqueous NaHCO₃, andsaturated aqueous NaCl before being dried (MgSO₄) and concentrated underreduced pressure. The title compound 85.0 mg (67%), was isolated bycolumn chromatography (20-50% EtOAc-hexanes) as a colorless solid.

[0777]¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.5 Hz), 7.09 (2H, d, J=8.5 Hz),6.40 (1H, s), 2.19 (2H, q, J=7.2 Hz), 1.18-1.24 (4H, m), 1.12 (3H, t,J=7.2 Hz).

[1-(4-Bromophenyl)-cyclopropyl]-propylamine (Intermediate 118)

[0778] To a solution of N-[1-(4-bromophenyl)-cyclopropyl]-propionamide(Intermediate 117, 85.0 mg, 0.32 mmol) in THF (5 mL) at 0° C. was addedBH₃—Me₂S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). Thesolution was heated to 55° C. for 17 hours, cooled to room temperature,saturated aqueous NaHCO₃ was added and the resulting mixture was stirredfor 2 hours. This mixture was extracted with EtOAc and the combinedorganic layers were washed with H₂O and saturated aqueous NaCl beforebeing dried (MgSO₄) and concentrated under reduced pressure. The titlecompound was isolated by column chromatography (10-30% EtOAc-hexanes).

[0779]¹H NMR (CDCl₃) δ: 7.42 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz),2.46 (2H, t, J=7.3 Hz), 1.40 (2H, m), 0.98 (2H, m), 0.86 (5H, m).

Propyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 119)

[0780] Using General Procedure D;[1-(4-bromophenyl)-cyclopropyl]-propylamine (Intermediate 118, 100.0 mg,0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(13.0 mg, 0.06 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (48.0 mg, 0.06 mmol). Theresulting reaction mixture was heated to 70° C. for 5 days. The titlecompound (80.0 mg, 75%) was isolated by chromatography (0 -10%EtOAc-hexanes) as an orange oil.

[0781]¹H NMR (CDCl₃) δ: 7.41 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz),2.45 (2H, t, J=7.3 Hz), 1.39 (2H, m), 0.98 (2H, m), 0.87 (2H, m), 0.84(3H, t, J=7.3 Hz), 0.24 (9H, s).

[1-(4-Ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120)

[0782] Using General Procedure E;propyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 119, 80.0 mg, 0.30 mmols) in methanol (8 mL) was treatedwith potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight atambient temperature. The crude alkyne (58 mg, 100%) was used directly inthe next reaction.

[0783]¹H NMR (CDCl₃) δ: 7.44 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz),3.05 (1H, s), 2.46 (2H, t, J=7.3 Hz), 1.41 (2H, m), 1.00 (2H, m), 0.90(2H, m), 0.86 (3H, t, J=7.3 Hz).

Ethyl 4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound107, General Formula 2)

[0784] Using General Procedure F;[1-(4-ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120, 38.0mg, 0.19 mmol) and ethyl-4-iodo benzoate (Reagent A, 58.0 mg, 0.21 mmol)in triethyl amine (6 mL) was treated with copper(I)iodide (8.0 mg, 0.04mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (5-15% EtOAc-hexanes) afforded 40.0mg (61%) of the title compound as an orange oil.

[0785]¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz),7.49 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.5 Hz), 4.39 (2H, q, J=7.1 Hz),2.49 (2H, t, J=7.3 Hz), 1.46 (2H, m), 1.41 (3H, t, J=7.1 Hz), 1.01 (2H,m), 0.89 (2H, m), 0.87 (3H, t, J=7.3 Hz).

4-[4-(1-Propylamino-cyclopropyl)-phenylethynyl]-benzoic acid (Compound108, General Formula 2)

[0786] Using General Procedure I; a solution of ethyl4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 107,40.0 mg, 0.12 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution)and stirred overnight at room temperature. Work-up afforded 25.0 mg(69%) of the title compound as a solid.

[0787]¹H NMR (d₆-DMSO) δ: 7.97 (2H, d, J=8.5 Hz), 7.65 (2H, d, J=8.5Hz), 7.50 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 2.39 (2H, t, J=7.3Hz), 1.37 (2H, m), 1.00 (2H, m), 0.93 (2H, m), 0.84 (3H, t, J=7.3 Hz).

[1-(4-Bromophenyl)-cyclopropyl]-dipropylamine (Intermediate 121)

[0788] To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate116) in CH₃CN/HOAc (5 mL, 9:1, v/v) and THF 3 mL at 0° C. was addedpropionaldehyde (277.0 mg, 4.95 mmols) and NaCNBH₃ (153.0 mg, 2.47mmols). The reaction was warmed to room temperature and after 5 hoursquenched with H₂O. The pH of the solution was adjusted to 8-9 usingaqueous NaOH and extracted with EtOAc. The combined extracts were washedwith H₂O and saturated aqueous NaCl, dried (MgSO₄) and concentratedunder reduced pressure. The title compound, 190.0 mg (56%), was isolatedby column chromatography (2-5% EtOAc-hexanes).

[0789]¹H NMR (CDCl₃) δ: 7.42 (2H, d, J=8.3 Hz), 7.18 (2H, d, J=8.3 Hz),2.39 (4H, t, J=7.3 Hz), 1.62-1.40 (4H, m), 0.96 (2H, m), 0.86 (6H, t,J=7.3 Hz), 0.80 (2H, m).

Dipropyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 122)

[0790] Using General Procedure D;[1-(4-bromophenyl)-cyclopropyl]-dipropylamine (Intermediate 121, 150.0mg, 0.50 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). Theresulting reaction mixture was heated to 70° C. for 5 d. The titlecompound was isolated by chromatography (0-3% EtOAc-hexanes).

[0791]¹H NMR (CDCl₃) δ: 7.35 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.3 Hz),2.39 (4H, t, J=7.3 Hz), 1.55-1.42 (4H, m), 0.96 (2H, m), 0.88-0.79 (8H,m), 0.25 (9H, s).

[1-(4-Ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123)

[0792] Using General Procedure E;dipropyl-[1-(4-trimethylsilanylethynyl- phenyl)-cyclopropyl]-amine(Intermediate 122, 45.0 mg, 0.14 mmols) in methanol (5 mL) was treatedwith potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight atambient temperature. The crude alkyne (34 mg, 100%) was used directly inthe next reaction.

[0793]¹H NMR (CDCl₃) δ: 7.42 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz),2.40(4H, t, J=7.3 Hz), 1.53-1.40 (4H, m), 0.96 (2H, m), 0.90-0.79 (8H,m).

Ethyl 4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate(Compound 109, General Formula 2)

[0794] Using General Procedure F;[1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0mg, 0.16 mmol) and ethyl-4-iodo benzoate (Reagent A, 59.0 mg, 0.21 mmol)in triethyl amine (6 mL) was treated with copper(I)iodide (13.0 mg, 0.07mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded thetitle compound as a yellow oil.

[0795]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.2 Hz),7.49 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 4.39 (2H, q, J=7.1 Hz),2.43 (4H, t, J=7.3 Hz), 1.52-1.42 (4H, m), 1.41 (3H, t, J=7.1 Hz), 0.99(2H, m), 0.88-0.83 (8H, m).

4-[4-(1-Dipropylamino-cyclopropyl)-phenylethynyl]-benzoic Acid (Compound110, General Formula 2)

[0796] Using General Procedure I; a solution of ethyl4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL)was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded32.0 mg (70%) of the title compound as a colorless solid.

[0797]¹H NMR (d₆-DMSO) δ: 7.98 (2H, d, J=8.3 Hz), 7.67 (6H, m),3.05-2.89 (4H, m), 1.98 (2H, m), 1.72 (4H, m), 1.23 (2H, m), 0.88 (6H,t, J=7.3 Hz).

Benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124) andDibenzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 125)

[0798] A solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate116, 244.0 mg, 1.15 mmols) and benzyl bromide (255.0 mg, 1.50 mmols) in4 mL DMF was stirred at 85° C. for 6 hours, cooled to room temperatureand stirred overnight. The solution was diluted with H₂O and the pHadjusted to 8-9 with aqueous NaOH. The solution was extracted with EtOAcand the combined organic layers were washed with H₂O and saturatedaqueous NaCl, dried (MgSO₄) and concentrated under reduced pressure.Column chromatography (5-10% EtOAc-Hexanes) afforded 110 mg (32%) of theN-benzyl amine.

[0799]¹H NMR (CDCl₃) δ: 7.48 (2H, d, J=8.4 Hz), 7.30-7.23 (7H, m), 3.68(2H, s), 1.07 (2H, m), 0.93 (2H, m); and 100 mg (22%) of theN,N-dibenzyl amine, ¹H NMR (CDCl₃) δ: 7.55 (2H, d, J=8.3 Hz), 7.40-7.19(12H, m), 3.61 (4H, s), 0.87 (2H, m), 0.71 (2H, m).

Benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 126)

[0800] Using General Procedure D;benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 110.0mg, 0.36 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). Theresulting reaction mixture was heated to 70° C. for 5 d. The titlecompound 85 mg (74%) was isolated by chromatography (1-10%EtOAc-hexanes).

[0801]¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.3 Hz), 7.31-7.22 (7H, m), 3.67(2H, s), 1.06 (2H, m), 0.94 (2H, m), 0.26 (9H, s).

Benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127)

[0802] Using General Procedure E;benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 126, 85.0 mg, 0.27 mmol) in methanol (5 mL) was treatedwith potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight atambient temperature. The crude alkyne (65 mg, 100%) was used directly inthe next reaction.

[0803]¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=7.9 Hz), 7.32 (2H, d, J=7.9 Hz),7.23 (5H, m), 3.68 (2H, s), 3.08 (1H, s), 1.07 (2H, m), 0.95 (2H, m).

Ethyl 4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound111, General Formula 2)

[0804] Using General Procedure F;benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127, 65.0mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol)in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added and thereaction mixture was stirred overnight at room temperature. Columnchromatography (2-5% EtOAc-hexanes) afforded 90 mg (90%) of the titlecompound as an orange solid.

[0805]¹H NMR (CDCl₃) δ: 8.05 (2H, d, J=8.3 Hz), 7.61 (2H, d, J=8.3 Hz),7.55 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.32-7.22 (5H, m), 4.40(2H, q, J=7.1 Hz), 3.72 (2H, s), 1.42 (2H, t, J=7.1 Hz), 1.01 (2H, m),0.99 (2H, m)

4-[4-(1-Benzylamino-cyclopropyl)-phenylethynyl]-benzoic acid (Compound112, General Formula 2)

[0806] Using General Procedure I; a solution of ethyl4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 111,75.0 mg, 0.19 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) wastreated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 35.0 mg(50%) of the title compound as a colorless solid.

[0807]¹H NMR (CD₃OD) δ: 7.93 (2H, d, J=8.3 Hz), 7.61-7.51 (6H, m),7.32-7.23 (5H, m), 3.98 (2H, s), 1.33(2H, m), 1.19 (2H, m).

Dibenzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 128)

[0808] Using General Procedure D;dibenzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 125, 45.0mg, 0.11 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.35 g, 3.6 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). Theresulting reaction mixture was heated to 70° C. for 5d. The titlecompound 40 mg (88%) was isolated by chromatography (hexanes).

[0809]¹H NMR (CDCl₃) δ: 7.52 (2H, d, J=8.3 Hz), 7.36-7.24 (12H, m), 3.60(4H, s), 0.87 (2H, m), 0.67 (2H, m), 0.29 (9H, s).

Dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129)

[0810] Using General Procedure E;dibenzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine(Intermediate 128, 100.0 mg, 0.26 mmol) in methanol (5 mL) was treatedwith potassium carbonate (60.0 mg, 0.44 mmol) and stirred overnight atambient temperature. The crude alkyne (80 mg, 99%) was used directly inthe next reaction.

[0811]¹H NMR (CDCl₃) δ: 7.53 (2H, d, J=7.9 Hz), 7.36 (2H, d, J=7.9 Hz),7.28-7.25 (10H, m), 3.62 (4H, s), 3.11 (1H, s), 0.88 (2H, m), 0.68 (2H,m).

Ethyl 4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate(Compound 113, General Formula 2)

[0812] Using General Procedure F;dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129, 40.0mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol)in triethylamine (5 mL) was treated with copper(I)iodide (8.0 mg, 0.04mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and thereaction mixture was stirred overnight at room temperature. Columnchromatography (2-5% EtOAc-hexanes) afforded the title compound as anoil.

[0813]¹H NMR (CDCl₃) δ: 8.04 (2H, d, J=8.5 Hz), 7.79 (4H, m), 7.42 (2H,d, J=7.9 Hz), 7.29-7.17 (10H, m), 4.40 (2H, q, J=7.1 Hz), 3.63 (4H, s),1.42 (3H, t, J=7.1 Hz), 0.88 (2H, m), 0.73 (2H, m).

4-[4-(1-Dibenzylamino-cyclopropyl)-phenylethynyl]-benzoic Acid (Compound114, Formula 2)

[0814] Using General Procedure I; a solution of ethyl4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound113, 48.0 mg, 0.10 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL)was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded42.0 mg (93%) of the title compound as a colorless solid.

[0815]¹H NMR (d₆-DMSO) δ: 7.98 (2H, d, J=8.2 Hz), 7.67 (2H, d, J=8.2Hz), 7.64 (2H, d, J=7.9 Hz), 7.47 (2H, d, J=7.9 Hz), 7.28-7.20 (10H, m),3.57 (4H, s), 0.84 (2H, m), 0.69 (2H, m).

Benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130)

[0816] To a solution of benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine(Intermediate 124, 100.0 mg, 0.33 mmol) in 5 mL of acetone was addedK₂CO₃ (91 mg, 0.66 mmol) and iodomethane (2.28 g, 16.1 mmols). Theresulting mixture was stirred at 25° C. for 20 hours, diluted with Et₂O,and washed with H₂O and saturated aqueous NaCl. The solution was dried(MgSO₄) and concentrated under reduced pressure to give 90 mg (86%) ofthe title compound.

[0817]¹H NMR (CDCl₃) δ: 7.47 (2 H, d, J=8.5 Hz), 7.29-7.18 (7H, m), 3.53(2H, s), 2.07 (3H, s), 1.07 (2H, m), 0.86 (2H, m).

Benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-methylamine(Intermediate 131)

[0818] Using General Procedure D;benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130,90.0 mg, 0.28 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (6.0 mg, 0.03 mmol) and then sparged with argon for 5minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then addedfollowed by dichlorobis(triphenylphosphine)palladium(II) (20.0 mg, 0.03mmol). The resulting reaction mixture was heated to 70° C. for 5 days.The title compound 80 mg (84%) was isolated by chromatography (0-2%EtOAc-hexanes).

[0819]¹H NMR (CDCl₃) δ: 7.46 (2H, d, J=8.2 Hz), 7.32-7.18 (7H, m), 3.52(2H, s), 2.06 (3H, s), 1.06 (2H, m), 0.87(2H, m), 0.26 (9H, s).

Benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132)

[0820] Using General Procedure E;benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-methylamine(Intermediate 131, 80.0 mg, 0.24 mmol) in methanol (5 mL) was treatedwith potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight atambient temperature. The crude alkyne (60 mg, 99%) was used directly inthe next reaction.

[0821]¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.33-7.21 (7H, m), 3.55(2H, s), 3.08 (1H, s), 2.08 (3H, s), 1.07 (2H, m), 0.89 (2H, m).

Ethyl 4-{4-[1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate(Compound 115, General Formula 2)

[0822] Using General Procedure F;benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132,70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg,0.10 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (65 mg, 0.10 mmol) was added and thereaction mixture was stirred overnight at room temperature. Columnchromatography (2-5% EtOAc-hexanes) afforded 86 mg (75%) of the titlecompound as an oil.

[0823]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz),7.53 (2H, d, J=8.2 Hz), 7.36 (2H, d, J=8.2 Hz), 7.25 (5H, m), 4.39 (2H,q, J=7.1 Hz), 3.57 (2H, s), 2.10 (3H, s), 1.41 (3H, t, J=7.1 Hz), 1.10(2H, m), 0.92 (2H, m).

4-[4-(1-Benzylmethylamino-cyclopropyl)-phenylethynyl]-benzoic Acid(Compound 116, General Formula 2)

[0824] Using General Procedure I; a solution of ethyl4-{4-[1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate(Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded45.0 mg (75%) of the title compound as a solid.

[0825]¹H NMR (d₆-DMSO) δ: 7.96 (2H, d, J=8.3 Hz), 7.66 (2H, d, J=8.3Hz), 7.58 (2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.2 Hz), 7.29-7.18 (5H, m),3.52 (2H, s), 2.00 (3H, s),1.02 (2H, m), 0.87 (2H, m).

(4-Bromo-2-methyl-phenyl)-methanol (Intermediate 133)

[0826] A solution of methyl 4-bromo-2-methyl-benzoate (1.05 g, 4.58mmols) in 10 mL of Et₂O was cooled to 0° C. and treated with LiAlH₄(177.0 mg, 4.58 mmols), stirred for 3 hours, and then carefully quenchedwith H₂O. The mixture was extracted with Et₂O and the combined organiclayers were washed with H₂O and saturated aqueous NaCl, dried (MgSO₄),and concentrated under reduced pressure. The title compound, 830.0 mg(90%), was isolated by column chromatography (10-30% EtOAc-hexanes) as acolorless oil.

[0827]¹H NMR (CDCl₃) δ: 7.30 (2H, m), 7.18 (1H, d, J=8.8 Hz), 4.57 (2H,d, J=5.5 Hz), 2.27 (3H, s), 2.13 (1H, t, J=5.5 Hz).

(4-Bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134)

[0828] To a solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate133, 500.0 mg, 2.48 mmols), in 10 mL THF was added triethylamine (374.0mg, 3.70 mmols) and chlorotrimethylsilane (297.0 mg, 2.70 mmols). Theresulting solution was stirred for 17 hours at 25° C. and then treatedwith H₂O and extracted with Et₂O. The combined organic layers werewashed with H₂O, 10% aqueous HCl, saturated NaHCO₃, and saturated NaClbefore being dried (MgSO₄) and concentrated under reduced pressure. Thetitle compound, 550.0 mg (81%), was isolated by column chromatography(5% EtOAc-hexanes) as a colorless oil.

[0829]¹H NMR (CDCl₃) δ: 7.35-7.28 (3H, m), 4.64 (2H, s), 2.29 (3H, s),0.20 (9H, s).

2-Methyl-4-trimethylsilanylethynyl-1-trimethylsilanyloxymethyl-benzene(Intermediate 135)

[0830] Using General Procedure D;(4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). Theresulting reaction mixture was heated to 70° C. for 5 days. The titlecompound (380.0 mg, 65%) was isolated by chromatography (0-2%EtOAc-hexanes) as an orange oil.

[0831]¹H NMR (CDCl₃) δ: 7.31 (3H, m), 4.64 (2H, s), 2.24 (3H, s), 0.24(9H, s), 0.15 (9H, s).

(4-Ethynyl-2-methyl-phenyl)-methanol (Intermediate 136)

[0832] Using General Procedure E;2-methyl-4-trimethylsilanylethynyl-1-trimethylsilananyloxymethyl-benzene(Intermediate 135, 380.0 mg, 1.30 mmols) in methanol (10 mL) was treatedwith potassium carbonate (180.0 mg, 1.3 mmol) and stirred overnight atambient temperature. The crude alkyne was purified by columnchromatography (5-20% EtOAc-hexanes) to give 100.0 mg (34%) of the titlecompound.

[0833]¹H NMR (CDCl₃) δ: 7.06 (3H, m), 4.42 (2H, d, J=5.2 Hz), 2.81 (1H,s), 2.05 (3H, s), 1.59 (1H, t, J=5.2 Hz).

Ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-benzoate (Compound 117,General Formula 6)

[0834] Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol(Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate(Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treatedwith copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (20-40% EtOAc-hexanes) afforded 130.0mg (99%) of the title compound as an orange solid.

[0835]¹H NMR (CDCl₃) δ: 7.98 (2H, d, J=8.2 Hz), 7.56 (2H, d, J=8.2 Hz),7.36 (3H, m), 4.65 (2H, s), 4.36 (2H, q, J=7.1 Hz), 2.40 (1H, s), 2.30(3H, s), 1.39 (3H, t, J=7.1 Hz).

Ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate (Intermediate137)

[0836] A solution of ethyl4-(4-hydroxymethyl-3-methyl-phenylethynyl)-benzoate (Compound 117, 130.0mg, 0.44 mmol) and triphenylphosphine (150.0 mg, 0.57 mmol) in 5 mLCH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (101.0 mg, 0.57 mmol)was added in 5 portions over 20 minutes. The solution was warmed to 25°C. and stirred for 17 hours. The reaction was quenched by the additionof dilute aqueous NaHCO₃. The resulting mixture was extracted with Et₂Oand the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (Na₂SO₄) and concentrated under reducedpressure. The title compound, 120.0 mg (76%), was isolated by columnchromatography (2-5% EtOAc-hexanes) as a colorless solid.

[0837]¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.1 Hz), 7.56 (2H, d, J=8.1 Hz),7.32 (3H, m), 4.48 (2H, s), 4.38 (2H, q, J=7.1 Hz), 2.40 (3H, s), 1.39(3H, t, J=7.1 Hz).

Ethyl 4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoate(Compound 118, General Formula 6)

[0838] A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF wastreated with NaH (11.0 mg, 0.44 mmol) and heated to 90° C. After 1 h asolution of ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate(Intermediate 137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added andstirring at 90° C. continued for 1 hour. The solution was cooled to roomtemperature and concentrated under reduced pressure. The title compound,90.0 mg (71%) was isolated by column chromatography (20-100%EtOAc-hexanes) as a colorless solid.

[0839]¹H NMR (CDCl₃) δ: 8.02 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz),7.51 (1H, s), 7.40 (1H, s), 7.36 (1H, dd,J=1.2, 7.9 Hz), 7.10 (1H, s),6.93 (1H, d, J=7.9 Hz), 6.88 (1H, t, J=1.7 Hz), 5.12 (2H, s), 4.38 (2H,q, J=7.1 Hz), 2.27 (3H, s), 1.40 (3H, t, J=7.1 Hz).

4-(4-Imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoic Acid (Compound119, General Formula 6)

[0840] Using General Procedure I; a solution of ethyl4-(4-imidazol-1-ylmethyl-3-methyl-phenylethynyl)-benzoate (Compound 118,82.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) wastreated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution)and stirred overnight at room temperature. Work-up afforded 51.0 mg(68%) of the title compound as a solid.

[0841]¹H NMR (d₆-DMSO) δ: 9.20 (1H, s), 7.97 (2H, d, J=8.2 Hz), 7.73(2H, m), 7.65 (2H, d, J=8.2 Hz), 7.52 (1H, s), 7.46 (1H, d, J=7.9 Hz),7.13 (1H, d, J=7.9 Hz), 5.50 (2H, s), 2.32 (3H, s).

4-Bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138)

[0842] A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol)in 5 mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (309.0 mg,1.74 mmol) was added in 5 portions over 20 minutes. The solution waswarmed to 25° C. and stirred for 17 hours. The reaction was quenched bythe addition of dilute aqueous NaHCO₃. The resulting mixture wasextracted with Et₂O and the combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. The title compound, 350.0 mg (84%), was isolatedby column chromatography (2-3% EtOAc-hexanes) as a colorless oil.

[0843]¹H NMR (CDCl₃) δ: 7.32 (1H, d, J=2.0 Hz), 7.29 (1H, dd, J=2.0, 7.9Hz), 7.15 (1H, d, J=7.9 Hz), 4.43 (2H, s), 2.37 (3H, s).

1-(4-Bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139)

[0844] A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF wastreated with NaH (20.0 mg, 0.86 mmol) and heated to 90° C. After 1 h asolution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138,190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90° C.continued for 1 hour. The solution was cooled to room temperature andconcentrated under reduced pressure. The title compound, 160.0 mg (88%)was isolated by column chromatography (5% MeOH-EtOAc) as a colorlesssolid.

[0845]¹H NMR (CDCl₃) δ: 7.46 (1H, s), 7.34 (1H, dd, J=1.8 Hz), 7.30 (1H,dd, J=1.8, 8.2 Hz), 7.08 (1H, t, J=1.2 Hz), 6.83 (1H, t, J=1.2 Hz), 6.80(1H, d, J=8.2 Hz), 5.03 (2H, s), 2.23 (3H, s).

1-(2-Methyl-4-trimethylsilanylethynyl-benzyl)-1H-imidazole (Intermediate140)

[0846] Using General Procedure D;1-(4-bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139, 160.0 mg,0.64 mmol) in triethylamine (8 mL) was treated with copper(I)iodide(12.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes.Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then added followed bydichlorobis(triphenylphosphine)palladium(II) (45.0 mg, 0.07 mmol). Theresulting reaction mixture was heated to 70° C. for 5 days. The titlecompound (140.0 mg, 82%) was isolated by chromatography (5% MeOH-EtOAc )as an orange oil.

[0847]¹H NMR (CDCl₃) δ: 7.53 (1H, s), 7.38 (1H, s), 7.34 (1H, d, J=8.0Hz), 7.15 (1H, s), 6.94 (1H, s), 6.91 (1H, d, J=8.0 Hz), 5.14 (2H, s),2.29 (3H, s), 0.31 (9H, s).

1-(4- Ethynyl-2-methyl-benzyl)-1H-imidazole (Intermediate 141)

[0848] Using General Procedure E;1-(2-methyl-4-trimethylsilanylethynyl-benzyl)-1H-imidazole (Intermediate140, 140.0 mg, 0.53 mmols) in methanol (5 mL) was treated with potassiumcarbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambienttemperature. The crude alkyne (105 mg, 100%) was used directly in thenext reaction.

[0849]¹H NMR (CDCl₃) δ: 7.49 (1H, s), 7.35 (1H, s), 7.31 (1H, dd, J=1.7,7.9 Hz), 7.10 (1H, s), 6.69 (1H, d, J=7.9 Hz), 6.85 (1H, t, J=1.2 Hz),5.14 (2H, s), 3.08 (1H, s), 2.26 (3H, s).

Methyl[4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetate(Compound 120, General Formula 6)

[0850] Using General Procedure F;1-(4-ethynyl-2-methyl-benzyl)-1H-imidazole (Intermediate 141, 101.0 mg,0.53 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 145.0 mg, 0.53mmol) in triethylamine (5 mL) was treated with copper(I)iodide (34.0 mg,0.18 mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (124 mg, 0.18 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (5% MeOH-EtOAc) afforded 45.0 mg(25%) of the title compound as an orange oil.

[0851]¹H NMR (CDCl₃) δ: 7.47 (3H, m), 7.35 (3H, m), 7.27 (3H, m), 6.91(1H, d, J=7.3 Hz), 5.11 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 2.26 (3H,s).

[4-(4-Imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetic acid(Compound 121, General Formula 6)

[0852] Using General Procedure I; a solution of methyl[4-(4-imidazol-1-ylmethyl-3-methyl-phenylethynyl)-phenyl]-acetate(Compound 120, 45.0 mg, 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran(2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueoussolution) and stirred overnight at room temperature. Work-up afforded30.0 mg (70%) of the title compound as a pale-orange solid.

[0853]¹H NMR (d₄-MeOH) δ: 8.97 (1H, s), 7.60 (2H, d J=8.8 Hz), 7.47 (3H,m), 7.41 (1H, d, J=7.9 Hz), 7.30 (2H, d, J=7.9 Hz), 7.23 (1H, d, J=7.9Hz), 5.51 (2H, s), 3.64 (2H, s), 2.33 (3H, s).

1-Isopropyl-3-methoxy-benzene (Intermediate 142)

[0854] To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mLof acetone was added K₂CO₃ (7.50 g, 54.3 mmols) and iodomethane (10.3 g,72.5 mmols). The resulting solution was heated to 50° C. and stirred for18 hours, cooled to room temperature, and concentrated under reducedpressure. The residual oil was dissolved in Et₂O and washed with H₂O,saturated aqueous NaHCO₃, and saturated aqueous NaCl before being dried(MgSO₄) and concentrated under reduced pressure. The crude methyl etherwas used without further purification.

[0855]¹H NMR (CDCl₃) δ: 7.22 (1H, t, J=8.1 Hz), 6.84-6.72 (3H, m), 3.81(3H, s), 2.88 (1H, septet, J=7.0 Hz), 1.25 (6H, d, J=7.0 Hz).

1-Bromo-2-isopropyl-4-methoxy-benzene (Intermediate 143)

[0856] A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142,3.50 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CCl₄ wastreated with N-bromosuccinimide (4.98 g, 28.0 mmols) at 35° C. for 18hours. An additional portion of N-bromosuccinimide (830.0 mg, 4.46mmols) was added and stirring continued for 6 hours. The mixture wascooled to room temperature, H₂O was added, and the mixture was filteredto remove the solids. The mixture was extracted with E₂O and thecombined organic layers were washed with 10% aqueous HCl, H₂O, saturatedaqueous NaHCO₃, and saturated NaCl before being dried (MgSO₄) andconcentrated under reduced pressure. Column chromatography (2.5%EtOAc-hexanes) afforded 4.34 g (81%) of the title compound as apale-yellow oil.

[0857]¹H NMR (CDCl₃) δ: 7.41 (1H, d, J=8.8 Hz), 6.82 (1H, d, J=2.6 Hz),6.61 (1H, dd, J=2.6, 8.8 Hz), 3.79 (3H, s), 3.31 (1H, septet, J=6.7 Hz),1.23 (6H, d, J=6.7 Hz).

4-Bromo-3-isopropyl-phenol (Intermediate 144)

[0858] To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene(Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CH₂Cl₂ at −78° C. wasadded BBr₃ (4.81 g, 19.2 mmols; 19.2 mL of a 1M solution in CH₂Cl₂).After stirring for 3 hours at −78° C. the solution was warmed to 0° C.for 3 hours and then at 25° C. for 1 hour before being quenched withH₂O. The mixture was diluted with Et₂O and washed with H₂O and saturatedaqueous NaCl, dried (Na₂SO₄) and concentrated under reduced pressure.Column chromatography (2.5-10% EtOAc-hexanes) afforded the titlecompound as a colorless oil.

[0859]¹H NMR (CDCl₃) δ: 7.38 (1H, d, J=8.5 Hz), 6.79 (1H, d, J=2.9 Hz),6.57 (1H, dd, J=2.9, 8.5 Hz), 3.31 (1H, septet, J=7.0 Hz), 1.22 (6H, d,J=7.0 Hz).

(4-Bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl-silane (Intermediate145)

[0860] A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13g, 5.25 mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols),and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25° C.for 3 hours. The solution was diluted with H₂O and extracted with Et₂Oand the combined organic layers were washed with H₂O, saturated aqueousNaCl, and dried (MgSO₄) before being concentrated under reducedpressure. Column chromatography (1-2% EtOAc-hexanes) afforded 1.50 g(87%) of the title compound as a colorless oil.

[0861]¹H NMR (CDCl₃) δ: 7.32 (1H, d, J=8.8 Hz), 6.73 (1H, d, J=3.0 Hz),6.52 (1H, dd, J=3.0, 8.8 Hz), 3.26 (1H, septet, J=6.7 Hz), 1.19 (6H, d,J=6.7 Hz), 0.96 (9H, s), 0.17 (6H, s).

4-(Tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde(Intermediate 146)

[0862] A solution of (4-bromo-3-isopropyl-phenoxy)-tert-butyl-dimethylsilane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E₂O was cooled to−78° C. and treated with tert-butyllithium (401.0 mg, 6.26 mmols; 3.7 mLof a 1.7M solution in pentane). After 30 minutes the reaction wasquenched with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature.The solution was diluted with H₂O, extracted with Et₂O and the combinedorganic layers washed with H₂O and saturated aqueous NaCl before beingdried (MgSO₄) and concentrated under reduced pressure. Columnchromatography (2% EtOAc -hexanes) afforded 480.0 mg (55%) of the titlecompound as a colorless oil.

[0863]¹H NMR (CDCl₃) δ: 10.19 (1H, s), 7.72 (1H, d, J=8.5 Hz), 6.85 (1H,d, J=2.3 Hz), 6.77 (1H, dd, J=2.3, 8.5 Hz), 3.97 (1H, septet, J=6.7 Hz),1.27 (6H, d, J=6.7 Hz), 1.00 (9H, s), 0.25 (6H, s).

4-Hydroxy-2-isopropyl-benzaldehyde (Intermediate 147)

[0864] To a solution of4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde(Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0° C. was addedtetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL of a 1M solutionin THF). The pale-yellow solution was stirred for 30 minutes andquenched by the addition of ice cold H₂O. The mixture was extracted withEt₂O and the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (Na₂SO₄) and concentrated under reducedpressure. Column chromatography (20% EtOAc-hexanes) afforded 500.0 mg(96%) of the title compound as a colorless solid.

[0865]¹H NMR (CDCl₃) δ: 10.15 (1H, s), 7.79 (1H, d, J=8.5 Hz), 6.95 (1H,d, J=2.3 Hz), 6.86 (1H, dd, J=2.3, 8.5 Hz), 3.96 (1H, septet, J=6.7 Hz),1.29 (6H, d, J=6.7 Hz).

4-Formyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate(Intermediate 148)

[0866] A solution of 4-hydroxy-2-isopropyl-benzaldehyde (Intermediate147, 300.0 mg, 1.83 mmol) in 10 mL of CH₂Cl₂ was cooled to 0° C. and toit was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine(754.0 mg, 1.92 mmol) and triethylamine (592.0 mg, 5.85 mmols). Theresulting solution was warmed to room temperature and stirred for 4.5hours. The reaction was quenched by the addition of H₂O and the mixtureextracted with EtOAc and the combined organic layers were washed with10% aqueous HCl, saturated aqueous NaHCO₃, H₂O, and saturated aqueousNaCl. The solution was dried (MgSO₄) and concentrated under reducedpressure. The title compound was isolated by column chromatography(5-10% EtOAc-hexanes) as a colorless oil, 470.0 mg (87%).

[0867]¹H NMR (CDCl₃) δ: 10.37 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.33 (1H,d, J=2.3 Hz), 7.26 (1H, dd, J=2.3, 8.5 Hz), 4.00 (1H, septet, J=6.7 Hz),1.33 (6H, d, J=6.7 Hz),

4-Hydroxymethyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate(Intermediate 149)

[0868] To a solution of 4-formyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL MeOHat 0° C. was added NaBH₄ (72.0 mg, 1.91 mmols). After stirring 2 hoursat 0° C. the reaction was carefully quenched with H₂O and extracted withEt₂O. The combined organic layers were washed with H₂O and saturatedaqueous NaCl, dried (MgSO₄), and concentrated under reduced pressure.The title compound was isolated by column chromatography (5-10%EtOAc-hexanes) as a colorless oil, 355.0 mg (90%).

[0869]¹H NMR (CDCl₃) δ: 7.45 (1H, d, J=8.5 Hz), 7.17 (1H, d, J=2.7 Hz),7.08 (1H, dd, J=2.7, 8.5 Hz), 4.74 (2H, d, J=5.3 Hz), 3.21 (1H, septet,J=7.0 Hz), 2.12 (1H, t, J=5.3 Hz), 1.24 (6H, d, J=7.0 Hz).

4-(Tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl1,1,1-trifluoro-methansulfonate (Intermediate 150)

[0870] A solution of 4-hydroxymethyl-3-isopropyl-phenyl1,1,1-trifluoro-methansulfonate (Intermediate 149, 760.0 mg, 2.55mmols), chloro-tert-butyl-dimethylsilane (470.0 mg, 3.18 mmols), andimidazole (225.0 mg, 3.25 mmols) in 6 mL DMF was stirred at 25° C. for17 hours. The solution was diluted with H₂O and extracted with Et₂O andthe combined organic layers were washed with 10% aqueous HCl, saturatedaqueous NaHCO₃, H₂O, and saturated aqueous NaCl, and dried (MgSO₄)before being concentrated under reduced pressure. Column chromatography(2-5% EtOAc-hexanes) afforded 970.0 mg (92%) of the title compound as acolorless oil.

[0871]¹H NMR (CDCl₃) δ: 7.49 (1H, d, J=8.5 Hz), 7.10 (1H, d, J=2.3 Hz),7.06 (1H, dd, J=2.3, 8.5 Hz), 4.75 (2H, s), 3.10 (1H, septet, J=6.7 Hz),1.21 (6H, d, J=6.7 Hz), 0.93 (9H, s), 0.10 (6H, s).

1-(Tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-4-trimethylsilanylethynyl-benzene(Intermediate 151)

[0872] To a solution of4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl1,1,1-trifluoro-methansulfonate (Intermediate 150, 970.0 mg, 2.35 mmols)in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then addedfollowed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09mmol). The resulting reaction mixture was heated to 95° C. for 20 hours.The solution was cooled to room temperature and concentrated underreduced pressure. The title compound (200.0 mg, 78%) was isolated bychromatography (0-25% EtOAc-hexanes) as an orange oil.

[0873]¹H NMR (CDCl₃) δ: 7.37-7.25 (3H, m), 4.75 (2H, s), 3.08 (1H,septet, J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 0.92 (9H, s), 0.25 (9H, s),0.09 (6H, s).

Tert-butyl-(4-ethynyl-2-isopropyl-benzyloxy)-dimethyl-silane(Intermediate 152)

[0874] Using General Procedure E;1-(tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-4-trimethylsilanylethynyl-benzene(Intermediate 151, 850.0 mg, 2.36 mmols) in methanol (25 mL) was treatedwith potassium carbonate (250.0 mg, 1.81 mmols) and stirred overnight atambient temperature. The crude alkyne (650 mg, 95%) was used directly inthe next reaction.

[0875]¹H NMR (CDCl₃) δ: 7.41-7.25 (3H, m), 4.77 (2H, s), 3.07 (1H,septet, J=7.0 Hz), 3.05 (1H, s), 1.22 (6H, d, J=7.0 Hz), 0.94 (9H, s),0.11 (6H, s).

Ethyl4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-benzoate(Intermediate 153)

[0876] Using General procedure F;tert-butyl-(4-ethynyl-2-isopropyl-benzyloxy)-dimethyl-silane(Intermediate 152, 300.0 mg, 1.04 mmols) and ethyl-4-iodo benzoate(Reagent A, 287.0 mg, 1.04 mmols) in triethylamine (8 mL) was treatedwith copper(I)iodide (50.0 mg, 0.26 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (182 mg, 0.26mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-4% EtOAc-hexanes) afforded 310.0mg (68%) of the title compound as an orange solid.

[0877]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz),7.48-7.37 (3H, m), 4.80 (2H, s), 4.39 (2H, q, J=7.1 Hz), 3.14 (1H,septet, J=6.8 Hz), 1.40 (3H, t, J=7.1 Hz), 1.27 (6H, d, J=6.8 Hz), 0.96(9H, s), 0.12 (6H, s).

Methyl{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Intermediate 154)

[0878] Using General Procedure F;tert-butyl-(4-ethynyl-2-isopropyl-benzyloxy)-dimethyl-silane(Intermediate 152, 355.0 mg, 1.26 mmols) andmethyl-(4-iodophenyl)-acetate (Reagent B, 349.0 mg, 1.26 mmols) intriethylamine (8 mL) was treated with copper(I)iodide (60.0 mg, 0.32mmol) and sparged with argon for 5 minutes.Dichlorobis(triphenylphosphine)palladium(II) (222 mg, 0.32 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (2-5% EtOAc-hexanes) afforded 288.0mg (66%) of the title compound as an orange oil.

[0879]¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.5 Hz), 7.43-7.35 (3H, m), 7.25(2H, d, J=8.5 Hz), 4.77 (2H, s), 3.69 (3H, s), 3.63 (2H, s), 3.11 (1H,septet, J=6.7 Hz), 1.25 (6H, d, J=6.7 Hz), 0.94 (9H, s), 0.10 (6H, s).

Ethyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-benzoate (Compound122, General Formula 6)

[0880] To a solution of ethyl4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-benzoate(Intermediate 153, 310.0 mg, 0.71 mmol) in 4 mL THF at 0° C. was addedtetrabutylammonium fluoride (371.0 mg, 1.42 mmols; 1.4 mL of a 1Msolution in THF). The pale-yellow solution was stirred for 10 minutesand quenched by the addition of ice cold H₂O. The mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (20-30% EtOAc-hexanes)afforded 200.0 mg (87%) of the title compound as a colorless solid.

[0881]¹H NMR (CDCl₃) δ: 7.98 (2H, d, J=8.5 Hz), 7.58 (2H, d, J=8.5 Hz),7.48 (1H, s), 7.35 (2H, m), 4.71 (2H, s), 4.35 (2H, q, J=7.1 Hz), 3.19(1H, septet, J=7.0 Hz), 2.51 (1H, s), 1.39 (3H, t, J=7.1 Hz), 1.25 (6H,d, J=7.0 Hz).

Methyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Compound 123, General Formula 6)

[0882] To a solution of methyl{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate(Intermediate 154, 288.0 mg, 0.66 mmol) in 5 mL THF at 0° C. was addedtetrabutylammonium fluoride (471.0 mg, 1.80 mmols; 1.8 mL of a 1Msolution in THF). The pale-yellow solution was stirred for 15 minutesand quenched by the addition of ice cold H₂O. The mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (5-10% EtOAc-hexanes)afforded 180.0 mg (85%) of the title compound as a colorless solid.

[0883]¹H NMR (CDCl₃) δ: 7.48 (3H, m), 7.32 (2H, m), 7.24 (2H, d, J=8.5Hz), 4.69 (2H, s), 3.68 (3H, s), 3.62 (2H, s), 3.18 (1H, septet, J=7.0Hz), 2.21 (1H, s), 1.25 (6H, d, J=7.0 Hz).

Ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-benzoate(Intermediate 155)

[0884] A solution of ethyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-benzoate (Compound 122,200.0 mg, 0.62 mmol) and triphenylphosphine (211.0 mg, 0.81 mmol) in 5mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (144.0 mg, 0.81mmol) was added in 5 portions over 20 minutes. The solution was warmedto 25° C. and stirred for 17 hours. The reaction was quenched by theaddition of dilute aqueous NaHCO₃. The resulting mixture was extractedwith Et₂O and the combined organic layers were washed with H₂O andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. The title compound, 220.0 mg (93%), was isolatedby column chromatography (5% EtOAc-hexanes) as a pale-yellow solid.

[0885]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz),7.48 (1H, s), 7.31 (2H, m) 4.55 (2H, s), 4.39 (2H, q, J=7.1 Hz), 3.29(1H, septet, J=7.0 Hz), 1.40 (3H, t, J=7.1 Hz), 1.30 (6H, d, J=7.0 Hz).

Methyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Intermediate 156)

[0886] A solution of methyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol)in 5 mL CH₂Cl₂ was cooled to 0° C. and N-bromosuccinimide (130.0 mg,0.73 mmol) was added in 5 portions over 20 minutes. The solution waswarmed to 25° C. and stirred for 17 hours. The reaction was quenched bythe addition of dilute aqueous NaHCO₃. The resulting mixture wasextracted with Et₂O and the combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. The title compound, 212.0 mg (98%), was isolatedby column chromatography (5-10% EtOAc-hexanes) as a pale-yellow oil.

[0887]¹H NMR (CDCl₃) δ: 7.48 (3H, m), 7.28 (4H, m), 4.55 (2H, s), 3.69(3H, s), 3.63 (2H, s), 3.28 (1H, septet, J=7.0 Hz), 1.30 (6H, d, J=7.0Hz).

Ethyl[4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate(Compound 124, General Formula 6)

[0888] A solution of ethyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-benzoate (Intermediate 155,120.0 mg, 0.31 mmol) and 1-acetylimidazole (36.0 mg, 0.33 mmol) in 5 mLCH₃CN was heated at 65° C. for 4 hours and then at 55° C. for 16 hours.The solution was cooled to room temperature, diluted with H₂O and madebasic by addition of Na₂CO₃, and extracted with EtOAc. The combinedorganic layers were washed with H₂O and saturated aqueous NaCl, dried(MgSO₄), and concentrated under reduced pressure. Column chromatography(1% Et₃N in 5% MeOH-EtOAc) afforded 75.0 mg (65%) of the title compoundas a colorless solid.

[0889]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz),7.53 (1H, d, J=1.5 Hz), 7.49 (1H, s), 7.35 (1H, dd, J=1.5, 7.9 Hz), 7.09(1H, bs), 6.98 (1H, d, J=7.9 Hz), 6.85 (1H, bs), 5.19 (2H, s), 4.39 (2H,q, J=7.1 Hz), 3.08 (1H, septet, J=6.8 Hz), 1.40 (3H, t, J=7.1 Hz), 1.20(6H, d, J=6.8 Hz).

Methyl[4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Compound 125, General Formula 6)

[0890] A solution of methyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Intermediate 156, 72.0 mg, 0.19 mmol) and 1-acetylimidazole (22.0 mg,0.20 mmol) in 5 mL CH₃CN was heated at 65° C. for 8 h and then at 55° C.for 16 hours. The solution was cooled to room temperature, diluted withH₂O and made basic by addition of Na₂CO₃, and extracted with EtOAc. Thecombined organic layers were washed with H₂O and saturated aqueous NaCl,dried (MgSO₄), and concentrated under reduced pressure. Columnchromatography (0.5% Et₃N in 5% MeOH-EtOAc) afforded 40.0 mg (58%) ofthe title compound as a colorless solid.

[0891]¹H NMR (CDCl₃) δ: 7.49 (4H, m), 7.33 (1H, dd, J=1.5, 7.9 Hz), 7.28(2H, d, J=8.5 Hz), 7.08 (1H, t, J=1.2 Hz), 6.95 (1H, d, J=7.9 Hz), 6.84(1H, t, J=1.2 Hz), 5.17 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 3.06 (1H,septet, J=6.8 Hz), 1.20 (6H, d, J=6.8 Hz).

[4-(4-Imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoicAcid (Compound 126, General Formula 6)

[0892] Using General Procedure I; a solution of ethyl[4-(4-imidazol-1-ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate(Compound 124, 75.0 mg, 0.20 mmol) in ethanol (4 mL) and tetrahydrofuran(1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 68.0 mg (88%) of the title compound as a colorless solid.

[0893]¹H NMR (d₄-MeOH) δ: 9.01 (1H, s), 8.01 (2H, d, J=8.2 Hz),7.63-7.57 (5H, m), 7.44 (1H, d, J=7.9 Hz), 7.29 (1H, d, J=7.9 Hz), 5.59(2H, s), 3.17 (1H, septet, J=6.8 Hz), 1.20 (6H, d, J=6.8 Hz).

[4-(4-Imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-aceticacid (Compound 127, General Formula 6)

[0894] Using General Procedure I; a solution of methyl[4-(4-imidazol-1-ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate(Compound 125, 40.0 mg, 0.11 mmol) in ethanol (4 mL) and tetrahydrofuran(1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 22.0 mg (52%) of the title compound as a colorless solid.

[0895]¹H NMR (d₄-MeOH) δ: 9.02 (1H, bs), 7.62 (1H, t, J=1.4 Hz), 7.58(2H, m), 7.49 (2H, d, J=8.2 Hz), 7.43 (1H, dd, J=1.5, 7.9 Hz), 7.31 (3H,m), 5.58 (2H, s), 3.68 (2H, s), 3.16 (1H, septet, J=6.7 Hz), 1.18 (6H,d, J=6.7 Hz).

4-Bromo-N-cyclopropyl-2-methyl-benzamide (Intermediate 157)

[0896] A solution of 4-bromo-2-methylbenzoic acid and SOCl₂ was refluxedfor 3 hours, cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in 30 mL CH₂Cl₂ and combined withcyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0mmols). The solution was stirred for 18 hours and then diluted withEtOAc before being washed with 5% aqueous HCl, saturated NaHCO₃, andsaturated aqueous NaCl. The solution was dried (MgSO₄) and concentratedunder reduced pressure leaving the title compound as a colorless solid.

[0897]¹H NMR (CDCl₃) δ: 7.34 (1H, d, J=2.3 Hz), 7.28 (1H, dd, J=2.3, 8.2Hz), 7.13 (1H, d, J=8.2 Hz), 6.10 (1H, bs), 2.85 (1H, m), 2.37 (3H, s),0.85 (2H, m), 0.59 (2H, m).

(4-Bromo-2-methyl-benzyl)-cyclopropyl-amine (Intermediate 158)

[0898] To a solution of 4-bromo-N-cyclopropyl-2-methyl-benzamide(Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH₃.SMe₂(1.08 g, 14.24 mmols). The solution was heated to 60° C. for 6 hours,cooled to room temperature and carefully treated with saturated aqueousNa₂CO₃ (30 mL) and stirred for 17 hours. This mixture was extracted withEtOAc and the combined organic layers were washed with H₂O, saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. The title compound was isolated by column chromatography(10-15% EtOAc-hexanes).

[0899]¹H NMR (CDCl₃) δ: 7.26 (2H, m), 7.12 (1H, d, J=7.9 Hz), 3.76 (2H,s), 2.31 (3H, s), 2.14 (1H, m), 0.44 (2H, m), 0.36 (2H, m).

(4-Bromo-2-methyl-benzyl)-cyclopropyl-ethyl-amine (Intermediate 159)

[0900] A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine(Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0mmols), and K₂CO₃ (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at60° C. for 18 hours. The mixture was cooled to room temperature, dilutedwith H₂O, and extracted with EtOAc. The combined organic layers werewashed with H₂O and saturated aqueous NaCl before being dried (MgSO₄)and concentrated under reduced pressure. The title compound was isolatedby column chromatography (2.5% EtOAc-hexanes).

[0901]¹H NMR (CDCl₃) δ: 7.23 (2H, m), 7.12 (1H, d, J=7.6 Hz), 3.62 (2H,s), 2.56 (2H, q, J=7.3 Hz), 2.29 (3H, s), 1.75 (1H, m), 1.04 (3H, t,J=7.3 Hz), 0.39 (2H, m), 0.30 (2H, m).

Cyclopropyl-ethyl-(2-methyl-4-trimethylsilanylethynyl-benzyl)-amine(Intermediate 160)

[0902] Using General Procedure D;(4-bromo-2-methyl-benzyl)-cyclopropyl-ethyl-amine (Intermediate 159,620.0 mg, 2.31 mmols) in triethylamine (8 mL) was treated withcopper(I)iodide (44.0 mg, 0.23 mmol) and then sparged with argon for 15minutes. Trimethylsilylacetylene (1.04 g, 10.6 mmols) was then addedfollowed by dichlorobis-(triphenylphosphine)palladium(II) (162.0 mg,0.23 mmol). The resulting reaction mixture was heated to 70° C. for 5days. The title compound (650.0 mg, 98%) was isolated by chromatography(1-4% EtOAc-hexanes).

[0903]¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.20 (2H, m), 3.65 (2H, s), 2.55(2H, q, J=7.3 Hz), 2.28 (3H, s), 1.74 (1H, m), 1.03 (3H, t, J=7.3 Hz),0.36 (2H, m), 0.27 (2H, m), 0.24 (9H, s).

Cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161)

[0904] Using General Procedure E;cyclopropyl-ethyl-(2-methyl-4-trimethylsilanylethynyl-benzyl)-amine(Intermediate 160, 650.0 mg, 2.30 mmols) in methanol (10 mL) was treatedwith potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight atambient temperature. The crude alkyne (495 mg, 99%) was used directly inthe next reaction.

[0905]¹H NMR (CDCl₃) δ: 7.32 (1H, s), 7.21 (2H, m), 3.66 (2H, s), 3.01(1H, s), 2.56 (2H, q, J=7.3 Hz), 2.29 (3H, s), 1.76 (1H, m), 1.04 (3H,t, J=7.3 Hz), 0.40 (2H, m), 0.29 (2H, m).

Ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoate(Compound 128, General Formula 6)

[0906] Using General Procedure F;cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161,190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg,0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide(56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes.Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (3-5% EtOAc-hexanes) afforded thetitle compound.

[0907]¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.2 Hz), 7.56 (2H, d, J=8.2 Hz),7.31-7.24 (3H, m), 4.38 (2H, q, J=7.1 Hz), 3.68 (2H, s). 2.58 (2H, q,J=7.3 Hz), 2.32 (3H, s), 1.77 (1H, m), 1.39 (3H, t, J=7.1 Hz), 1.05 (3H,t, J=7.3 Hz), 0.39 (2H, m), 0.31 (2H, m).

Methyl(4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetate)(Compound 129, General Formula 6)

[0908] Using General Procedure F;cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161,300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B,388.0 mg, 1.41 mmols) in triethylamine (8 mL) was treated withcopper(I)iodide (67.0 mg, 0.35 mmol) and sparged with argon for 15minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 0.35mmol) was added and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (5-7% EtOAc-hexanes) afforded 270.0mg (53%) of the title compound as a pale-yellow oil.

[0909]¹H NMR (CDCl₃) δ: 7.47 (2H, d, J=7.9 Hz), 7.30-7.22 (5H, m), 3.70(3H, s), 3.68 (2H, s), 3.63 (2H, s), 2.58 (2H, q, J=7.3 Hz), 2.32 (3H,s), 1.77 (1H, m), 1.05 (3H, t, J=7.3 Hz), 0.39 (2H, m), 0.30 (2H, m).

4-{4-[(Cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoicAcid: (Compound 130, General Formula 6)

[0910] Using General Procedure I; a solution of ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoate(Compound 128, 130.0 mg, 0.36 mmol) in ethanol (5 mL) andtetrahydrofuran (5 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0mL of a 3N aqueous solution) and stirred overnight at room temperature.Work-up afforded 115.0 mg (96%) of the title compound as a colorlesssolid.

[0911]¹H NMR (d₆-acetone) δ: 8.05 (2H, d, J=8.2 Hz), 7.64 (2H, d, J=8.2Hz), 7.32 (3H, m), 3.73 (2H, s), 2.59 (2H, q, J=7.3 Hz), 2.35 (3H, s),1.83 (1H, m), 1.05 (3H, t, J=7.3 Hz), 0.38 (2H, m), 0.27 (2H, m).

(4-{4-[(Cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-aceticAcid (Compound 131, General Formula 6)

[0912] Using General Procedure I; a solution of methyl(4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetate(Compound 129, 140.0 mg, 0.39 mmol) in ethanol (5 mL) andtetrahydrofuran (5 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0mL of a 3N aqueous solution) and stirred overnight at room temperature.Work-up followed by HPLC (Partisil-10 pac 10% H₂O—CH₃CN) afforded thetitle compound.

[0913]¹H NMR (CDCl₃) δ: 7.45 (2H, d, J=8.2 Hz), 7.25 (5H, m), 4.16 (2H,m), 3.82 (2H, s), 3.56 (2H, s), 2.75 (2H, q, J=7.3 Hz), 2.30 (3H, s),1.86 (1H, m), 1.14 (3H, t, J=7.3 Hz), 0.54 (2H, m), 0.46 (2H, m).

Ethyl {4-(4-cyclopropylaminomethyl-3-isopropyl-phenylethynyl}-benzoate(Compound 132, General Formula 6)

[0914] A solution of ethyl[4-(4-bromomethyl-3-isopropyl-phenylethynyl)-benzoate (Intermediate 155,110.0 mg, 0.29 mmol) and cyclopropylamine (420.0 mg, 7.4 mmols) in EtOH(5 mL) was stirred at 25° C. for 6 hours and then concentrated underreduced pressure. The residue was dissolved in EtOAc and washed withsaturated aqueous NaHCO₃, H₂O and saturated aqueous NaCl. The solutionwas dried (MgSO₄) and concentrated under reduced pressure to give 103 mg(99%) of the title compound as an orange oil.

[0915]¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz),7.47 (1H, s), 7.30 (2H, m), 4.38 (2H, q, J=7.1 Hz), 3.89 (2H , s), 3.26(1H, septet, J=7.0 Hz), 2.17 (1H, m), 1.40 (3H, t, J=7.1 Hz), 1.26 (6H,d, J=7.0 Hz), 0.45 (2H, m), 0.39 (2H, m).

Ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate(Compound 133, General Formula 6)

[0916] To a solution of ethyl{4-(4-cyclopropylaminomethyl-3-isopropyl-phenylethynyl}-benzoate(Compound 132, 103.0 mg, 0.29 mmol) in 6 mL of acetone was added ethyliodide (67.0 mg, 0.43 mmol) and K₂CO₃ (79.0 mg, 0.57 mmol). The mixturewas stirred at 60° C. for 6 hours, cooled to room temperature andquenched by the addition of H₂O. The mixture was extracted with EtOAcand the combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried (MgSO₄) and concentrated under reducedpressure. Column chromatography (4-5% EtOAc-hexanes) afforded 68.0 mg(59%) of the title compound.

[0917]¹H NMR (CDCl₃) δ: 8.01 (2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz),7.44 (1H, s), 7.28 (2H, m), 4.39 (2H, q, J=7.1 Hz), 3.73 (2H, s), 3.55(1H, septet, J=6.6 Hz), 2.57 (2H, q, J=7.3 Hz), 1.75 (1H, m), 1.40 (3H,t, J=7.1 hz), 1.22 (6H, d, J=6.6 Hz), 1.05 (3H, t, J=7.3 Hz), 0.37 (2H,m), 0.28 (2H, m).

4-{4-[(Cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoicacid (Compound 134, General Formula 6)

[0918] Using General Procedure I; a solution of ethyl4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate(Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5Naqueous solution) and stirred overnight at room temperature and then at55° C. for 9 hours. Work-up followed by crystallization of the solidresidue from hot CH₃CN afforded 45.0 mg (72%) of the title compound as apale-yellow solid.

[0919]¹H NMR (d₆-acetone) δ: 8.05 (2H, d, J=8.1 Hz), 7.66 (2H, d, J=8.1Hz), 7.49 (1H, s), 7.32 (2H, m), 3.78 (2H, s), 3.44 (1H, septet, J=6.7Hz), 2.59 (2H, q, J=7.3 Hz), 1.80 (1H, m), 1.21 (6H, d, J=6.7 Hz), 1.05(3H, t, J=7.3 Hz), 0.40 (2H, m), 0.26 (2H, m).

Methyl[4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 4, General Formula 8)

[0920] Using General Procedure F;6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 13,190.0 mg, 0.96 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 245.0mg, 0.96 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide(46 mg, 0.24 mmol) and sparged with argon for 15 minutes.Dichlorobis(triphenylphosphine)palladium(II) (168 mg, 0.24 mmol) wasadded and the reaction mixture was stirred overnight at roomtemperature. Column chromatography (10-20% EtOAc-hexanes) afforded 250.0mg (75%) of the title compound as a pale-yellow solid.

[0921]¹H NMR (CDCl₃) δ: 7.99 (1H, d, J=7.9 Hz), 7.57 (1H, d, J=1.5 Hz),7.51 (2H, d, J=8.5 Hz), 7.43 (1H, dd, J=1.5, 7.9 Hz), 7.29 (2H, d, J=8.5Hz), 3.70 (3H, s), 3.65 (2H, s), 2.73 (2H, t, J=7.0 Hz), 2.04 (2H, t,J=7.0 Hz), 1.41 (6H, s).

Methyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 135, General Formula 4)

[0922] To a solution of methyl[4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 4) in 5 mL MeOH at 0° C. was added NaBH₄ (18.0 mg, 0.48 mmol).The reaction was stirred at 0° C. for 2 hours and then quenched by theaddition of H₂O. The solution was diluted with Et₂O and washed with H₂Oand saturated aqueous NaCl before being dried (MgSO₄) and the solventswere removed under reduced pressure. Column chromatography (20-40%EtOAc-hexanes) afforded 140.0 mg (87%) of the title compound as acolorless oil.

[0923]¹H NMR (CDCl₃) δ: 7.49 (3H, m), 7.39 (1H, d, J=7.9 Hz), 7.31 (1H,dd, J=1.5, 7.9 Hz), 7.25 (2H, d, J=8.2 Hz), 4.58 (1H, bs), 3.68 (3H, s),3.62 (2H, s), 2.05 (1H, m), 1.79 (2H, m), 1.60 (1H, m), 1.33 (3H, s),1.26 (3H, s).

Methyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate(Compound 136, General Formula 4)

[0924] A solution of methyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate(Compound 135, 140.0 mg, 0.40 mmol) and carbonyldiimidazole (136.0 mg,0.84 mmol) in 5 mL THF was heated to 65° C. for 48 hours. The solutionwas cooled to room temperature and concentrated under reduced pressure.The residue was dissolved in Et₂O and washed with 5% aqueous NaOH, H₂O,and saturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (5% MeOH—CH₂Cl₂) afforded50.0 mg (31%) of the title compound as a colorless solid.

[0925]¹H NMR (CDCl₃) δ: 7.57 (1H, d, J=1.5 Hz), 7.52-7.45 (3H, m), 7.27(3H, m), 7.08 (1H, s), 6.81 (2H, m), 5.30 (1H, t, J=5.8 Hz), 3.71 (3H,s), 3.65 (2H, s), 2.20 (2H, m), 1.75 (2H, m), 1.40 (3H, s), 1.36 (3H,s).

[4-(5-Imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-aceticAcid (Compound 137, General Formula 4)

[0926] Using General Procedure I; a solution of methyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate(Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated withNaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirredovernight at room temperature. Work-up afforded 40.0 mg (83%) of thetitle compound as a pale-orange solid.

[0927]¹H NMR (d₄-MeOH) δ: 8.93 (1H, s), 7.68 (1H, s), 7.61 (1H, s), 7.54(1H, s), 7.47 (2H, d, J=8.2 Hz), 7.31 (3H, m), 6.95 (1H, d, J=8.2 Hz),5.83 (1H, t, J=5.8 Hz), 3.68 (1H, s), 3.63 (1H, s), 2.38 (1H, m), 2.26(1H, m), 1.76 (2H, m), 1.45 (3H, s), 1.36 (3H, s).

Ethyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate(Compound 138, General Formula 4)

[0928] A solution of ethyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate(180.0 mg, 0.52 mmol) and carbonyldiimidazole (176.0 mg, 1.08 mmol) in 5mL THF was heated to 65° C. for 21 hours. The solution was cooled toroom temperature and concentrated under reduced pressure. The residuewas dissolved in Et₂O and washed with 55 aqueous NaOH, H₂O, andsaturated aqueous NaCl before being dried (Na₂SO₄) and concentratedunder reduced pressure. Column chromatography (5% MeOH—CH₂Cl₂) afforded50.0 mg (24%) of the title compound as a colorless solid.

[0929]¹H NMR (CDCl₃) δ: 8.03 (2H, d, J=7.9 Hz), 7.59 (3H, m), 7.46 (1H,s), 7.29 (1H, dd, J=1.5, 8.3 Hz), 7.09 (1H, s), 6.82 (1H, d, J=8.2 Hz),6.81 (1H, s), 5.31 (1H, t, J=5.8 Hz), 4.39 (2H, q, J=7.1 Hz), 2.20 (2H,m), 1.75 (2H, m), 1.40 (9H, m).

[4-(5-Imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoicAcid (Compound 139, General Formula 4)

[0930] Using General Procedure I; a solution of ethyl[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate(Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran(1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1Naqueous solution) and stirred overnight at room temperature. Work-upafforded 40.0 mg (87%) of the title compound as a colorless solid.

[0931]¹H NMR (d₄-MeOH) δ: 8.92 (1H, s), 8.04 (2H, d, J=8.2 Hz), 7.74(1H, d, J=1.5 Hz), 7.62 (3H, m), 7.57 (1H, t, J=1.5 Hz), 7.38 (1H, dd,J=1.5, 7.9 Hz), 6.97 (1H, d, J=7.9 Hz), 5.83 (1H, t, J=5.8 Hz), 2.33(2H, m), 1.78 (2H, m), 1.47 (3H, s), 1.39 (3H, s).

2-Isopropyl-4-trifluoromethanesulfonyloxy-benzyl Acetate (Intermediate162)

[0932] To a solution of 4-hydroxymethyl-3-isopropylphenyl1,1,1-trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol)in 5 mL CH₂Cl₂ was added acetyl chloride (75.0 mg, 0.96 mmol) andpyridine(101.0 mg, 1.38 mmols). After stirring for 3 hours at 25° C. thereaction was quenched by the addition of H₂O and the resulting mixtureextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl, dried (MgSO₄) and concentrated under reducedpressure. The title compound, 182 mg (84%), was isolated from theresidual oil by column chromatography (5-10% EtOAc-hexanes) as acolorless oil.

[0933]¹H NMR (CDCl₃) δ: 7.43 (1H, d, J=8.7 Hz), 7.19 (1H, d, J=2.7 Hz),7.09 (1H, dd, J=2.7, 8.5 Hz), 5.17 (2H, s), 3.18 (1H, septet, J=6.7 Hz),2.10 (3H, s), 1.26 (6H, d, J=6.7 Hz).

4-Isopropenyloxymethyl-3-isopropyl-phenyl1,1,1-trifluoromethanesulfonate (Intermediate 163)

[0934] Using General Procedure 1;2-isopropyl-4-trifluoromethanesulfonyloxy-benzyl acetate (Intermediate162, 182.0 mg, 0.54 mmols), and 1.1 mL of Tebbe's Reagent (159.0 mg,0.56 mmols) afforded 130.0 mg (72%) of the title compound as a colorlessoil after column chromatography (2-5% EtOAc-hexanes).

[0935]¹H NMR (CDCl₃) δ: 7.43 (1H, d, J=8.5 Hz), 7.18 (1H, d, J=2.6 Hz),7.09 (1H, dd, J=2.6, 8.5 Hz), 4.75 (2H, s), 3.98 (2H, s), 3.12 (1H,septet, J=6.7 Hz), 1.88 (3H, s), 1.25 (6H, d, J=Hz).

3-Isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl1,1,1-trifluoromethanesulfonate (Intermediate 164)

[0936] Using General Procedure 2;4-isopropenyloxymethyl-3-isopropylphenyl 1,1,1-trifluoromethanesulfonate(Intermediate 163, 130.0 mg, 0.39 mmol), Et₂Zn (272.0 mg, 2.2 mmols),and CH₂I₂ (702.0 mg, 2.6 mmols) in 3.0 mL Et₂O afforded 120.0 mg (89%)of the title compound as a colorless oil after column chromatography(4-5% EtOAc-hexanes).

[0937]¹H NMR (CDCl₃) δ: 7.39 (1H, d, J=8.5 Hz), 7.13 (1H, d, J=2.7 Hz),7.05 (1H, dd, J=2.7, 8.5 Hz), 4.54 (2H, s), 3.16 (1H, septet, J=6.7 Hz),1.47 (3H, s), 1.24 (6H, d, J=6.7 Hz), 0.86 (2H, m), 0.48 (2H, m).

[3-Isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane(Intermediate 165)

[0938] Using General Procedure D;3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol)in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argonfor 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was thenadded followed by dichlorobis(triphenylphosphine)palladium(II) (24.0 mg,0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60hours. The title compound 110.0 mg, (99%) was isolated by chromatography(0-1% EtOAc-hexanes).

[0939]¹H NMR (CDCl₃) δ: 7.36 (1H, s), 7.24 (2H, bs), 4.53 (2H, s), 3.11(1H, septet, J=6.7 Hz), 1.45 (3H, s), 1.22 (6H, d, J=6.7 Hz), 0.85 (2H,m), 0.44 (2H, m), 0.25 (9H, s).

4-Ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene(Intermediate 166)

[0940] Using General Procedure E;[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane(Intermediate 165, 110.0 mg, 0.37 mmol) in methanol (6 mL) was treatedwith potassium carbonate (80.0 mg, 0.58 mmol) and stirred overnight atambient temperature. The crude alkyne (84 mg, 100%) was used directly inthe next reaction.

[0941]¹H NMR (CDCl₃) δ: 7.55 (1H, s), 7.41 (2H, m), 4.68 (2H, s), 3.26(1H, septet, J=6.8 Hz), 3.18 (1H, s), 1.60 (3H, s), 1.37 (6H, d, J=6.8Hz), 0.99 (2H, m), 0.59 (2H, m).

Methyl{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate(Compound 140, General Formula 6)

[0942] Using General Procedure F;4-ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene(Intermediate 166, 78.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate(Reagent B, 94.0 mg, 0.34 mmol) in triethylamine (8 mL) was treated withcopper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5minutes. Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol)was added and the reaction mixture was stirred at room temperature for3.5 hours. Column chromatography (2-5% EtOAc-hexanes) afforded 77.0 mg(60%) of the title compound as a yellow oil.

[0943]¹H NMR (CDCl₃) δ: 7.49 (2H, d, J=8.2 Hz), 7.43 (1H, d, J=1.5 Hz),7.33-7.24 (4H, m), 4.55 (2H, s), 3.70 (3H, s), 3.63 (2H, s), 3.14 (1H,septet, J=6.8 Hz), 1.47 (3H, s), 1.25 (6H, d, J=6.8 Hz), 0.86 (2H, m),0.46 (2H, m).

{4-[3-Isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-aceticacid (Compound 141, Formula 6)

[0944] Using General Procedure I; a solution methyl{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate(Compound 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran(3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3Naqueous solution) and stirred overnight at room temperature. Work-up andpurification by HPLC (Partisil 10-pac, 10% H₂O/CH₃CN) afforded of thetitle compound as a colorless solid.

[0945]¹H NMR (CDCl₃) δ: 7.50 (2H, d, J=8.2 Hz), 7.43 (1H, s), 7.33-7.24(4H, m), 4.55 (2H, s), 3.65 (2H, s), 3.14 (1H, septet, J=6.7 Hz), 1.47(3H, s), 1.25 (6H, d, J=6.7 Hz), 0.87 (2H, m), 0.46 (2H, m).

2,6-Di-tert-butyl-4-trimethylsilanylethynyl-phenol: (Intermediate 167)

[0946] Following General Procedure D and using4-bromo-2,6-di-t-butyl-phenol (1.43 g, 5 mmol), triethyl amine (15 mL),anhydrous tetrahydrofuran (15 mL), copper(I)iodide (0.06 g, 0.31 mmol),trimethylsilyl acetylene (4.9 g, 50 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.18 g, 0.26 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using hexane as eluent, the title compound was obtained (1.35 g, 90%).

[0947]¹H NMR (300 MHz, CDCl₃): δ7.29 (s, 2H), 5.35 (s, 1H), 1.42 (s,18H), 0.24 (s, 9H).

(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-trimethyl-silane:(Intermediate 168)

[0948] A solution 2,6-di-tert-butyl-4-trimethylsilanylethynyl-phenol(Intermediate 167, 0.302 g, 1 mmol) in acetone (5 mL) was treated withpotassium carbonate (0.138 g, 1 mmol) and methyl iodide (0.142 g, 1mmol) and stirred overnight at room temperature. The volatiles weredistilled off in vacuo and the residue was purified by flash columnchromatography on silica gel (230-400 mesh) using ethyl acetate as theeluent to afford the title compound as a white solid (0.28 g, 90%).

[0949]¹H NMR (300 MHz, CDCl₃): δ7.41 (s, 2H), 3.70 (s, 3H), 1.49 (s,18H), 0.30 (s, 9H).

1,3-Di-tert-butyl-5-ethynyl-2-methoxy-benzene: (Intermediate 169)

[0950] Following General Procedure E and(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-trimethyl-silane(Intermediate 168, 0.28 g, 0.9 mmol), potassium carbonate (0.98 g, 7.1mmol) and methanol (10 mL) followed by flash column chromatography oversilica gel (230-400 mesh) using hexane as the eluent, the title compoundwas obtained (0.23 g, 100%). ¹H NMR (300 MHz, CDCl₃): δ7.46 (s, 2H),3.75 (s, 3H), 3.05 (s, 1H), 1.49 (s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic AcidMethyl ester: (Compound 142, General Formula 5)

[0951] Following General Procedure F and using1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.094g, 0.36 mmol), methyl-4-iodo phenyl acetate (Reagent B, 0.09 g, 0.32mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (5 mL),copper(I)iodide (0.02 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% ethyl acetate in hexane as the eluent, the title compound(0.114 g, 81%) was obtained as an oil.

[0952]¹H NMR (300 MHz, CDCl₃): δ7.52 (d, 2H, J=8.0 Hz), 7.46 (s, 2H),7.28 (d, 2H, J=8.2 Hz), 3.72 (s, 3H), 3.71(s, 3H), 3.66 (s, 2H), 1.47(s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic Acid:(Compound 143, General Formula 5)

[0953] Following General Procedure I and using[4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acidmethyl ester (Compound 142, 0.114 g, 0.29 mmol), 5M aqueous sodiumhydroxide solution (2 mL) and ethanol (4 mL), followed by preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phase,the title compound was obtained as a white solid (0.097 g, 88%).

[0954]¹H NMR (300 MHz, CDCl₃): δ7.55(d, 2H, J=8.0 Hz), 7.48 (s, 2H),7.30 (d, 2H, J=8.2 Hz), 3.74 (s, 3H), 3.69 (s, 2H), 1.49 (s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticAcid Methyl Ester: (Compound 144, General Formula 5)

[0955] Following General Procedure F and using1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.087g, 0.33 mmol), methyl-2-fluoro-4-iodo phenyl acetate (Reagent H, 0.088g, 0.30 mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (10 mL),copper(I)iodide (0.02 g, 0.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol)followed by flash column chromatography over silica gel (230-400 mesh)using 10% Ethyl acetate in hexane as the eluent, the title compound(0.122 g, 89%) was obtained.

[0956]¹H NMR (300 MHz, CDCl₃): δ7.46 (s, 2H), 7.33-7.24 (m, 3H), 3.75(s, 3H), 3.73(s, 3H), 3.72 (s, 2H), 1.48 (s, 18H).

[4-(3,5-Di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticAcid: (Compound 145, General Formula 5)

[0957] Following General Procedure I and using[4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticacid methyl ester (Compound 144, 0.122 g, 0.29 mmol), 5M aqueous sodiumhydroxide solution (1 mL) and ethanol (4 mL), followed preparativereverse phase HPLC using 10% water in acetonitrile as the mobile phase,the title compound was obtained as a white solid (0.077 g, 65%).

[0958]¹H NMR (300 MHz, CDCl₃): δ7.42 (s, 2H), 7.29-7.19 (m, 3H), 3.71(s, 2H), 3.69 (s, 3H), 1.43 (s, 18H).

What is claimed is:
 1. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X is O, S or NR where R is H, alkyl of 1 to 6 carbons,C₁₋₆-trialkylsilyl or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl,lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substitutedcycloalkyl of 3 to 6 carbons, Cl, Br, or I; Z is —C≡C—, —(CR₁═CR₁)_(n′)where n′ is an integer having the value 1-5, —CO—NR₁—, NR₁—CO—; —CO—O—,—O—CO—, —CS—NR₁—, NR₁—CS—, —CO—S—, —S—CO—, —N═N—; R₁ is independently Hor alkyl of 1 to 6 carbons; R₂ is independently H, alkyl of 1 to 6carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons,alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R₃ isindependently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substitutedalkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of1 to 6 carbons or benzyl; m is an integer having the values 0 to 3; R₇is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or loweralkyl substituted cycloalkyl of 1 to 6 carbons; n is an integer havingthe values of 1 to 4, and R₈ is H, alkyl of 1 to 6 carbons,—CH₂O(C₁₋₆-alkyl), or a cation of a pharmaceutically acceptable base. 2.A compound in accordance with claim 1 where A is phenyl, naphthyl,pyridyl, thienyl or furyl.
 3. A compound in accordance with claim 1where n is 0, 1 or
 2. 4. A compound in accordance with claim 1 where Zis —C≡C—, —CO—NR₁—, —CO—O—, or —(CR₁═CR₁)_(n′) where n′ is
 1. 5. Acompound in accordance with claim 1 where the Z group is attached to the4-position of the phenyl moiety.
 6. A compound in accordance with claim1 where X is O.
 7. A compound in accordance with claim 1 where Y is H,lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substitutedcycloalkyl, or halogen.
 8. A compound in accordance with claim 1 where Ais phenyl.
 9. A compound in accordance with claim 1 where n is
 1. 10. Acompound of the formula

wherein Y is branched-chain alkyl of 3 to 6 carbons; R₂is H or F; R₃ isbranched-chain alkyl of 3 to 6 carbons; R₇ is lower alkyl of 1 to 6carbons, and R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or acation of a pharmaceutically acceptable base.
 11. A compound inaccordance with claim 10 where Y is t-butyl.
 12. A compound inaccordance with claim 11 where R₃ is t-butyl.
 13. A compound inaccordance with claim 12 where R₇ is methyl.
 14. A compound inaccordance with claim 13 which is selected from the group consisting of[4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acid and[4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-aceticacid or a salt of said compound with a pharmaceutically acceptable base.15. A compound of the formula

wherein A is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups; X₂ is 1-imidazolyl, lower alkyl or halogen substituted1-imidazolyl, OR₇, SR₇ or NRR₇ where R is H, alkyl of 1 to 6 carbons orbenzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogensubstituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons, Cl, Br, or I; Z is —C≡C—, —(CR₁═CR₁)_(n′) where n′ is aninteger having the value 1-5, —CO—NR₁—, NR₁—CO—; —CO—O—, —O—CO—,—CS—NR₁—, NR₁—CS—, —CO—S—, —S—CO—, —N═N—; R₁ is independently H or alkylof 1 to 6 carbons; R₂ is independently H, alkyl of 1 to 6 carbons, F,Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons; R₃ is alkyl of 1 to 6 carbons,F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxyof 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is aninteger having the values 0 to 3; R₇ is H, alkyl of 1 to 6 carbons,cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to6 carbons or C₁₋₆-trialkylsilyl. n is an integer having the values of 0to 4, and R₈ is H, alkyl of 1 to 6 carbons, —CH₂O(C₁₋₆-alkyl), or acation of a pharmaceutically acceptable base.
 16. A compound inaccordance with claim 15 where A is phenyl, naphthyl, pyridyl, thienylor furyl.
 17. A compound in accordance with claim 15 where n is 0, 1 or2.
 18. A compound in accordance with claim 15 where Z is —C≡C—,—CO—NR₁—, —CO—O—, or —(CR₁═CR₁)_(n′) where n′ is
 1. 19. A compound inaccordance with claim 15 where the Z group is attached to the 4-positionof the phenyl moiety.
 20. A compound in accordance with claim 15 whereX₂ is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl. 21.A compound in accordance with claim 15 where Y is H, lower alkyl of 1 to3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen.22. A compound in accordance with claim 15 where A is phenyl.
 23. Acompound in accordance with claim 15 where n is
 1. 24. A compound of theformula

wherein R₃ is alkyl of 1 to 6 carbons; X₂ is 1-imidazolyl, OR₇, or NRR₇where R is alkyl of 1 to 6 carbons or cyclopropyl, and R₇ is alkyl of 1to 6 carbons, cyclopropyl or lower alkyl substituted cyclopropyl; n is 0or 1, and R₈ is H, alkyl of 1 to 6 carbons, or a cation of apharmaceutically acceptable base.
 25. A compound in accordance withclaim 24 wherein X₂ is 1-imidazolyl.
 26. A compound in accordance withclaim 25 wherein n is
 0. 27. A compound in accordance with claim 26which is selected from the group consisting of4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoic acid and[4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoicacid or a salt of said compound with a pharmaceutically acceptable baseor a C₁₋₆ alkyl ester of said compound.
 28. A compound in accordancewith claim 25 wherein n is
 1. 29. A compound in accordance with claim 28which is selected from the group consisting of[4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetic acidand [4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-aceticacid or a salt of said compound with a pharmaceutically acceptable baseor a C₁₋₆ alkyl ester of said compound.
 30. A compound in accordancewith claim 24 where X₂ is ethyl,cyclopropyl-N—.
 31. A compound inaccordance with claim 30 wherein n is
 0. 32. A compound in accordancewith claim 31 which is selected from the group consisting of4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoicand4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoicacid or a salt of said compound with a pharmaceutically acceptable baseor a C₁₋₆ alkyl ester of said compound.
 33. A compound in accordancewith claim 30 wherein n is
 1. 34. A compound in accordance with claim 33which is(4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-aceticacid or a salt of said compound with a pharmaceutically acceptable baseor a C₁₋₆ alkyl ester of said compound.
 35. A compound in accordancewith claim 24 where X₂ is (1-methyl)cyclopropyl-oxy.
 36. A compound inaccordance with claim 35 wherein n is
 1. 37. A compound in accordancewith claim 36 which is{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-aceticacid or a salt of said compound with a pharmaceutically acceptable baseor a C₁₋₆ alkyl ester of said compound.